Role of oestrogen in the regulation of bone turnover at the menarche

in Journal of Endocrinology
Author: Richard Eastell
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  • Academic Unit of Bone Metabolism, Division of Clinical Sciences (North), School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK

The rise in oestrogen levels at menarche in girls is associated with a large reduction in bone turnover markers. This reduction reflects the closure of the epiphyseal growth plates, the reduction in periosteal apposition and endosteal resorption within cortical bone, and in bone remodelling within cortical and cancellous bone. Oestrogen promotes these changes, in part, by promoting apoptosis of chondrocytes in the growth plate and osteoclasts within cortical and cancellous bone. The period of early puberty is associated with an increased risk of fracture, particularly of the distal forearm, and this may be related to the high rate of bone turnover. A late menarche is a consistent risk factor for fracture and low bone mineral density in the postmenopausal period; models that might explain this association are considered.

Abstract

The rise in oestrogen levels at menarche in girls is associated with a large reduction in bone turnover markers. This reduction reflects the closure of the epiphyseal growth plates, the reduction in periosteal apposition and endosteal resorption within cortical bone, and in bone remodelling within cortical and cancellous bone. Oestrogen promotes these changes, in part, by promoting apoptosis of chondrocytes in the growth plate and osteoclasts within cortical and cancellous bone. The period of early puberty is associated with an increased risk of fracture, particularly of the distal forearm, and this may be related to the high rate of bone turnover. A late menarche is a consistent risk factor for fracture and low bone mineral density in the postmenopausal period; models that might explain this association are considered.

Introduction

The decrease in the levels of oestrogen at the time of the menopause results in an increase in the rate of bone remodelling and this plays a major role in the development of postmenopausal osteoporosis. These changes are dwarfed by the large increase in bone turnover that occurs at the menarche (Fig. 1). Indeed, the changes in bone turnover are matched by the changes in bone mineral – up to 25% of total bone mineral accrual occurs over two years at the time of peak height velocity (Bailey et al. 1999). This review article will consider the role of oestrogen in the changes in bone turnover at the menarche, and the consequence of these changes to an individual’s risk of fracture.

The study of bone turnover

Methods

Most of the information about the changes in bone turnover at menarche and menopause come from the measurement of biochemical markers of bone turnover. These markers are measured in serum and urine and thus have the advantages that they can be measured repeatedly in an individual, they are relatively inexpensive, are non-invasive and reflect bone turnover in the whole skeleton. They have drawbacks in that they may not be specific to bone, and their levels may be determined by changes in the rate of clearance from the circulation.

The alternative methods for studying bone turnover include bone histomorphometry, calcium balance with kinetics, and radioisotope tracer methods. Bone histomorphometry is based on a bone biopsy, usually taken from the iliac crest. This method has the advantage that it allows the study of changes to the two major cell types, osteoblasts and osteoclasts, and if tetracycline labels are administered, it allows the rate of bone remodelling to be measured. The drawbacks are that the biopsy is invasive, that the biopsy site may not be representative of the entire skeleton, and that only two biopsies may be taken in an individual’s lifetime. Calcium balance studies involve an in-patient stay of several weeks on a fixed diet with the administration of a radioactive or stable tracer of calcium (or strontium). This method has the advantage that it relates to the whole body and that it gives an accurate estimate of balance, in contrast to the other two methods. However, the long hospital stay means this is a very expensive approach and requires great attention to detail, and there are few places which currently conduct such studies. Also, the mathematical models to estimate calcium kinetics have never been standardised.

Bone turnover markers

The bone turnover markers are products of the osteoblasts or osteoclasts. The osteoblasts synthesise many proteins, and several of these are unique to the osteoblasts. The immature osteoblasts secrete proteins such as the bone isoform of alkaline phosphatase (bone ALP) which is involved in the mineralisation of bone and the type I collagen propeptides from the C- and N-terminal (PICP, PINP). The latter are cleaved from type I procollagen after its secretion from the osteoblasts. The mature osteoblasts secrete osteocalcin (OC), the marker that is most specific to the osteoblasts.

The bone resorption markers are either degradation products of type I collagen, or the enzyme tartrate resistant acid phosphatase (TRACP). Hydroxyproline makes up a large part of the weight of collagen, but this amino acid is derived from other proteins, is absorbed from the diet, and there is no immunoassay and so its use as a bone resorption marker has fallen out of favour. The pyridinium crosslinks are formed between and within collagen molecules from lysine and hydroxylysine residues once the collagen fibres line up in a quarter stagger array. The crosslinks include pyridinoline (PYD) and deoxypyridinoline (DPD); these may be excreted in the urine in the free form, or attached to the terminal residues of the collagen molecule, the so called C- and N-terminal telopeptides (CTX and NTX).

These bone turnover markers may be measured in serum and urine (Table 1). Their measurement has been validated by the similar pattern with age in children (Fig. 1), the relationship to height velocity (see below), and by comparison with calcium kinetics, and compares well, even in children (Weaver et al. 1997).

Changes in bone turnover across life

There has been a great deal of investigation into the increase of 20 to 100% in bone turnover that occurs at the menopause. However, the levels of bone turnover at the menarche are up to ten times higher than in premenopausal women, and the levels in the neonate are even higher. The reason for the very high levels of bone turnover markers in childhood is that they reflect not only the process of bone remodelling, but also that of growth.

Changes in bone turnover at the menarche

Description

Bone turnover markers are high during childhood (relative to adulthood) and there is a further increase during puberty. With the onset of menarche, the markers all decline despite the high levels of insulin-like growth factor-I (IGF-I). Many studies have investigated markers of bone formation and resorption during childhood (Table 1). The changes in bone turnover with age are similar to those reported by bone histomorphometry (Parfitt et al. 2000). These studies consistently show that bone metabolism rates are greater in children compared with adults, with markers of bone formation and resorption being several times higher compared with adults. The magnitude of this increase can vary greatly between markers (Blumsohn et al. 1994). In the study by Blumsohn et al.(1994) bone ALP increased tenfold but PICP only increased threefold in pubertal girls compared with the adult reference range (Fig. 2).

Thus, the bone resorption marker, urinary NTX, is 330 nmol bone collagen equivalents (BCE)/mmol creatinine (Cr) in mid-puberty (Tanner (T) stages II and III), 80 at the end of puberty (stage V), and 30 in premenopausal women (Fig. 1).

A significant positive correlation between biochemical markers of bone turnover and height velocity has been described in several studies (Schiele et al. 1983, Kanzaki et al. 1992, Hertel et al. 1993, Bollen & Eyre 1994, Kubo et al. 1995, Marowska et al. 1996, Rauch et al. 1996, Sorva et al. 1997, Cadogan et al. 1998, Kikuchi et al. 1998, Bollen 2000). Longitudinal studies indicate that bone turnover markers are maximal during early puberty (TI to TIII) but the greatest mineral accrual occurs during mid to late puberty when markers are declining (Riis et al. 1985, Theintz et al. 1992, Del et al. 1994, Slemenda et al. 1994, Cadogan et al. 1998, Magarey et al. 1999). Cadogan et al.(1998) reported that bone turnover markers were correlated to height velocity and not with bone gain (Fig. 3). Therefore Szulc et al.(2000) suggest that bone turnover markers are likely to reflect statural growth rather than bone mineral accrual.

What processes do the markers reflect?

Bone remodelling is about three times higher in children as compared with adults (Parfitt et al. 2000). Thus, the increase in markers must be reflecting other processes. These include linear growth, which occurs at the epiphyseal growth plate, and modelling which includes changes in shape and axis. The growth plate results in the production of new trabecular bone, and modelling results in the production of new cortical bone by periosteal or endosteal apposition. The processes are directed by the daily stress stimulus; bone growth during puberty is a mechanically driven process, modulated by hormonal and dietary factors (Beaupre et al. 1990, van der Meulen et al. 2001). These mechanical forces ensure that the section modulus of bone closely follows body weight (and thus, muscle mass). The exquisite sensitivity of bone growth to the daily stress stimulus may explain why the benefits of physical activity before menarche are so much greater than after menarche (Kannus et al. 1995).

Linear growth continues until age 16 in girls and 18 in boys (Tanner 1975). Boys enter puberty two years later than girls and the accelerated growth phase lasts one year longer and hence boys are 10% taller than girls. Presumably, the greater increase in body weight and muscle mass in boys is providing a greater mechanical stimulus to bone and thus the total body bone mineral is 25% higher in girls than in boys at the end of puberty (Riggs et al. 2002). Some growth plates remain open until the age of 25, e.g. those in the posterior spinous processes. Modelling is maximal during puberty, continues until the third decade, and probably continues to a smaller extent throughout life. The continued opening of some growth plates and the continued increase in size of bones by modelling, such as the vertebrae (Henry et al. 2004), accounts for the higher levels of bone turnover markers in women in the third decade as compared with the fourth and fifth decades (Khosla et al. 1998).

Why do the changes differ between markers?

Not all markers behave the same. The increase in urinary free crosslinks (e.g. immunoreactive (i)FDPD) increase less than telopeptides (conjugated crosslinks e.g. NTX). This may relate to renal handling of free and conjugated crosslinks. It appears that up to half of free crosslinks are generated within the renal tubule from conjugated cross-links and that this process is rate limiting (Colwell & Eastell 1996). Thus the changes in free DPD tend to be damped. PICP increases less than PINP. This may relate to the induction of the mannose receptor by IGF-I; PINP is cleared by a different pathway, the scavenger receptor (Smedsrod et al. 1990). Finally, the markers may differ in their distribution – OC is rich in cortical bone (Ninomiya et al. 1990, Magnusson et al. 1999) while bone ALP is present in the growth plate (Tuckermann et al. 2000).

What is the role of oestrogen?

Growth, modelling and remodelling

Oestrogen has a biphasic effect on growth. By stimulating growth hormone (GH) production, it results in an increase in growth during puberty. This was well shown by Ross et al.(1983) who treated girls with Turner’s syndrome with ethinyl oestradiol. They found that low doses accelerated growth, whereas high doses slowed growth. Thus, at low doses, growth is accelerated but at high doses there is inhibition of growth and stimulation of fusion of the epiphyses (Parfitt 2002). The importance of oestrogen for the arrest of growth and closure of the growth plate is now recognised by the report of cases of delayed closure in men with oestrogen receptor deficiency (Smith et al. 1994) or aromatase deficiency (Morishima et al. 1995, Carani et al. 1997).

The effects of oestrogen on modelling are to inhibit periosteal apposition and stimulate endosteal apposition. It is thus a key mediator of the sexual dimorphism of bone and is the reason (along with the differences in linear growth, see above) why women have smaller bones relative to their size than men. The main effect of oestrogen on bone remodelling is to decrease it (see below).

Some studies report a strong negative correlation between oestradiol and bone turnover markers in girls during puberty (Blumsohn et al. 1994, Cadogan et al. 1998) although the finding is not universal (Rotteveel et al. 1997). This observation would be consistent with the known effects of oestradiol on the growth plate, the periosteum and remodelling.

How does oestrogen work?

The effect of oestrogen on bone remodelling is to decrease activation frequency and subsequent decrease in the numbers of osteoclasts and osteoblasts. The effects of oestrogen on the osteoclast are probably mainly indirect and mediated by products secreted by the osteoblast. These products include RANK-L (the ligand of the receptor activator of nuclear factor kappa B) and colony stimulating factor 1 (CSF-1). They regulate the differentiation of osteoclast precursors to osteoclasts, and then modulate the activity of the mature osteoclast and regulate its rate of apoptosis. Oestrogen binds to receptors on the osteoblasts and increases directly the production of osteoprotegerin (OPG) and decreases the production of CSF-1. Oestrogen decreases the secretion of the pro-inflammatory cytokines interleukin-1 and tumour necrosis factor-alpha by marrow monocytes and this results in decreased production of OPG and RANK-L by the osteoblasts, thereby decreasing the rate of production of osteoclasts, their activity and their survival (Riggs et al. 2002). It is possible that oestrogens also exert an anabolic effect on osteoblasts. The evidence for this action comes from histological and biochemical studies in oestrogen-deficient mice and humans (Tobias & Compston 1999). The effects on the growth plate have been studied in ovariectomised rabbits. Here oestrogen induces apoptosis of chondrocytes, resulting in arrest of linear growth (Weise et al. 2001). Oestrogen receptors (ER) (both α and β) have been identified on chondrocytes in the human growth plate cartilage and on osteoblasts on trabecular bone surfaces, which implies a direct action of oestrogen on longitudinal bone growth and bone formation (Kusec et al. 1998, Nilsson et al. 1999).

The effect of oestrogen on bone cells is mediated by both ERα and ERβ. Using ER knockout mouse experiments it is believed that the remodelling effects are mainly mediated by ERα, as are the growth plate effects, but the effects on the periosteum may be mediated by the ERβ (Riggs et al. 2002). Interestingly, the effects of biomechanical forces appear to be mediated by the oestrogen receptor α (Lanyon et al. 2004).

How does oestrogen interact with GH and IGF-I?

There are a number of ways in which oestrogen and GH interact. (1) Oestrogen increases GH secretion by the pituitary at puberty, and this increased production has direct and indirect effects (by increasing IGF-I) on bone growth, modelling and remodelling. The effect of oestrogen appears to be to augment growth hormone pulse amplitude (Veldhuis et al. 2004). (2) Growth hormone has a major effect on bone, mainly through the local generation of IGF-I. This stimulates the growth plate to increase the rate of growth. There are increases in IGF-I during childhood (Fig. 3), with peak levels during pubertal development in boys and girls (Luna et al. 1983, Silbergeld et al. 1986, Cara et al. 1987, Johansen et al. 1988, Costin et al. 1989, Argente et al. 1993, Blumsohn et al. 1994, Moreira-Andres et al. 1995, Sabatier et al. 1996, Cadogan et al. 1998, Libanati et al. 1999), and correlation with height velocity (Silbergeld et al. 1986, Juul et al. 1994). These studies also report that IGF-I correlates better with Tanner stage than with chronological age. GH and IGF-I increase the rate of bone remodelling. IGF-I stimulates periosteal apposition. (3) Oestrogen antagonises the effects of GH and of IGF-I on the growth plate by stimulating fusion of the epiphysis (Ho et al. 1987, Stanhope et al. 1988, Matkovic 1996, Caufriez 1997). It opposes its effects at the periosteum and on remodelling. (4) IGF-I lowers the levels of sex-hormone binding globulin, thus increasing bio-available oestradiol (Pfeilschifter et al. 1996); the consequence of this is to limit the actions of GH and IGF-I on bone.

What is the relevance to fracture risk?

Fractures at puberty relate to bone mineral density

Fracture rate increases greatly at puberty in boys and girls. It has been proposed that there is an asynchrony between the peak height velocity and peak increase in bone mineral accrual, that latter following the former by about one year (Cadogan et al. 1998). This could be the case, but there is a pitfall here – height is one dimensional, whereas bone mineral content is three-dimensional (it is distributed within the volume of bone).

The fracture rate around puberty (Fig. 4) is the highest during life (Bailey et al. 1989) – about one half of children sustain a fracture, and half of these are forearm fractures, mainly occurring during early puberty (Jones et al. 2002b). Also, these fractures have increased by between 30 and 60% in the past 30 years (Khosla et al. 2003).

What is the mechanism for these fractures? It was proposed that these resulted from high levels of physical activity, but this relationship is not proven (Blimkie et al. 1993). However, the risk of fracture relates to the level of bone mineral density (BMD) (Jones et al. 2002a, Ma & Jones 2003) and to low BMD in mothers. Indeed, the low BMD might be explained by a thin cortical shell due to endosteal resorption (Blimkie et al. 1993, Parfitt 1994, Ma & Jones 2003). The timing of the increase in fractures may relate to this increased cortical porosity in the distal radius, with calcium demand for bone growth being so high. Presumably, the signal for increased cortical remodelling is parathyroid hormone (PTH), as the levels of this hormone are higher in early than in late puberty (Cadogan et al. 1998) (Fig. 3). An increase in PTH would indicate that calcium supplementation might be beneficial; there have been several clinical trials of calcium or milk supplementation at this age showing benefits on bone mass (Johnston et al. 1992, Lloyd et al. 1993, Lee et al. 1994, Chan et al. 1995, Bonjour et al. 1997, Cadogan et al. 1997, Dibba et al. 2000, Rozen et al. 2003, Stear et al. 2003). These studies showed consistent results despite the differences in the ages of the subjects, forms of calcium used and in habitual calcium intakes. As yet, there have been no clinical trials with fracture as the endpoint.

Age at menarche is a major determinant of later fracture

A late menarche is a determinant of BMD in the older woman and a strong risk factor for fracture risk. For example, the relative risk of hip fracture in women who had their menarche after the age of 17 was 2.1 (Fujiwara et al. 1997), the relative risk of vertebral fracture in women who had their menarche after the age of 16 was 1.8 (Roy et al. 2003) and the relative risk of distal forearm fracture in women who had their menarche after the age of 15 was 1.5 (Silman 2003).

Late menarche was associated with low BMD at the lumbar spine (Rosenthal et al. 1989, Ito et al. 1995, Varenna et al. 1999), femoral neck (Gerdhem & Obrant 2004) and distal radius (Fox et al. 1993). Some of these effects could be mediated by changes in bone geometry, with a larger bone marrow cavity at the radius (Rauch et al. 1999) but no changes to femoral neck dimensions (Pasco et al. 1999).

There are two hypotheses that might explain this association (Fig. 5). The first of these relates to lifetime exposure to oestrogen. Thus, a woman with an early menarche would have more years of exposure to oestrogen. However, in the above studies age at menarche appears to have a stronger effect on fracture risk than age at menopause (Fujiwara et al. 1997, Roy et al. 2003, Silman 2003) and there is evidence that age at menarche is more strongly related to BMD than age at menopause (Gerdhem & Obrant 2004) although some work does not support this relationship (Ito et al. 1995, Varenna et al. 1999).

The second hypothesis is that the body habitus that is associated with early menarche is associated with low risk of fracture. Thus, girls who enter menarche earlier have higher body mass index (and thus serum leptin (Matkovic et al. 1997)). They soon establish regular menses (Vihko & Apter 1984) (supporting hypothesis one) and they tend to be shorter and heavier (by 4 kg, on average) (Garn et al. 1986). Slender stature is an important risk factor for hip and spine fracture (Meyer et al. 1995, Roy et al. 2003), and tallness is a risk factor for hip fracture (Meyer et al. 1995).

Conclusions

Are measurements of bone turnover markers helpful for a better understanding of the changes in bone during puberty? The case for supporting their use is based on the similarity in the changes across childhood and puberty with the changes assessed by bone histomorphometry (Fig. 1), on the strong relationship between the level of bone turnover markers and height velocity, and on the expected response of bone turnover markers to stimuli such as growth hormone therapy (Kanzaki et al. 1992). The case against supporting their use is that different markers increase to different extents during puberty, the correlation of bone turnover markers with calcium kinetic measurements is not as strong as in adults, and bone turnover markers do not correlate well with changes in bone mineral content. These tools are therefore useful, but their interpretation needs to be treated with caution and the measurement of several different markers in the same study is advised.

Table 1

List of the bone turnover markers and the supporting evidence for changes during childhood and puberty

Evidence for increased levels of bone turnover markers during childhood (relative to adulthood) and a further increase during puberty
Bone turnover marker
Bone formation(Blumsohn et al. 1994), (Eastell et al. 1992), (Cadogan et al. 1998), (Mora et al. 1999), (Magmusson et al. 1995), (Sorva et al. 1997), (Schiele et al. 1983), (van Hoof et al. 1990), (Trivedi et al. 1991), (Hertel et al. 1993), (Kanzaki et al. 1992), (Tobiume et al. 1997), (Kubo et al. 1995), (Libanati et al. 1999), (Slemenda et al. 1997), (Crofton et al. 1997), (Cole et al. 1985), (Tommasi et al. 1996), (Kikuchi et al. 1998), (Riis et al. 1985), (Johansen et al. 1988), (Gundberg et al. 1983), (Sabatier et al. 1996), (Bass et al. 1999), (Sen et al. 2000)
    Bone alkaline phosphatase (bone ALP)
 Osteocalcin (OC)
 Procollagen type I C- and N-propeptides(PICP and PINP)
Bone resorption(Blumsohn et al. 1994), (Eastell et al. 1992), (Cadogan et al. 1998), (Mora et al. 1998, 1999), (Beardsworth et al. 1990), (Ohishi et al. 1993), (Rauch et al. 1995, 1996), (Fujimoto et al. 1995), (Libanati et al. 1999), (Slemenda et al. 1997), (Crofton et al. 1997), (Shaw & Bishop 1995), (Tommasi et al. 1996), (Kikuchi et al. 1998), (Conti et al. 1998), (Bollen & Eyre 1994), (Bass et al. 1999), (Marowska et al. 1996)
    Hydroxyproline (Hyp)
 Galactosyl hydroxylysien (Gal-Hyl)
 Pyridinoline (PYD)
 Deoxypyridinoline (DPD)
 N- and C-telopeptides of type I collagen(NTX-I, CTX-I and CTX-MMP (ICTP))
 Tartrate-resistant acid phosphatase(TRACP)
Figure 1
Figure 1

Bone turnover is higher during childhood than adulthood. Note the very high levels of bone remodelling during infancy, and how bone turnover decreases rapidly after puberty, using (A) bone histomorphometry, bone formation rate with bone volume referent (BFR/BV), and (B) the urinary bone resorption marker, NTX. BCE, bone collagen equivalents; Curved lines, best-fitting fifth order polynomial; Straight line, simple linear regression line. Reproduced from Parfitt et al.(2000) with permission from Elsevier and from Mora et al.(1998) with permission from Springer-Verlag.

Citation: Journal of Endocrinology 185, 2; 10.1677/joe.1.06059

Figure 2
Figure 2

Biochemical markers of bone formation (shaded boxes) and resorption (open boxes) in mid-puberty (Tanner stages II and III) in girls relative to the mean level in adults. ALP, alkaline phosphatase; i, immunoreactive; w, wheat germ lectin; ICTP, type I collagen C-telopeptide; uGal-Hyl/Cr, urinary galactosyl hydroxylysine to creatine ratio. Data from Blumsohn et al.(1994).

Citation: Journal of Endocrinology 185, 2; 10.1677/joe.1.06059

Figure 3
Figure 3Figure 3Figure 3

The increase in serum oestradiol levels precede menarche and are associated with a slowing of growth velocity and a decrease in bone turnover markers. Note how the IGF-I levels continue to increase, despite the deceleration in height velocity. The maximum gain in bone mineral content occurs at menarche and subsequently serum PTH levels decline. (A) Change (Δ) in height (a), total body bone mineral content (TBBMC) (b) and bone mineral density (TBBMD) (c). (B) Levels of and change in serum bone ALP (immunoreactive (i)BAP) (a and b) and urinary free DPD (iFDpd) (c and d). (C) Levels of and change in serum parathyroid hormone (PTH) (a and b), oestradiol (E2) (c and d), and insulin-like growth factor I (IGF-I) (e and f) in healthy girls entering the study at ages 11 to 12 years, with 18 months of follow-up. Reproduced from Cadogan et al.(1998) with permission from the American Society for Bone and Mineral Research.

Citation: Journal of Endocrinology 185, 2; 10.1677/joe.1.06059

Figure 4
Figure 4

Fractures are common at the onset of puberty in boys and girls; they most commonly involve the distal forearm, as shown here. Reproduced from Khosla et al.(2003) with permission from the American Medical Association.

Citation: Journal of Endocrinology 185, 2; 10.1677/joe.1.06059

Figure 5
Figure 5

Two models for the mechanism underlying the association between early menarche and low risk of fracture. Model 2 shows the duration of reproductive life in a woman with early menarche and one with late menarche (and a period of anovulatory, irregular cycles). In this case, the woman with late menarche would have less lifetime exposure to oestrogen. However, fracture risk is greater in the woman with few reproductive years due to later menarche (b) than in the woman with few reproductive years due to early menopause (c).

Citation: Journal of Endocrinology 185, 2; 10.1677/joe.1.06059

The author declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

References

  • Argente J, Barrios V, Pozo J, Munoz MT, Hervas F, Stene M & Hernandez M 1993 Normative data for insulin-like growth factors (IGFs), IGF-binding proteins, and growth hormone-binding protein in a healthy Spanish pediatric population: age- and sex-related changes. Journal of Clinical Endocrinology and Metabolism 77 1522–1528.

    • Search Google Scholar
    • Export Citation
  • Bailey DA, Wedge JH, McCulloch RG, Martin AD & Bernhardson SC 1989 Epidemiology of fractures of the distal end of the radius in children as associated with growth. Journal of Bone and Joint Surgery of America 71 1225–1231.

    • Search Google Scholar
    • Export Citation
  • Bailey DA, Mckay HA, Mirwald RL, Crocker PR & Faulkner RA 1999 A six-year longitudinal study of the relationship of physical activity to bone mineral accrual in growing children: the university of Saskatchewan bone mineral accrual study. Journal of Bone and Mineral Research 14 1672–1679.

    • Search Google Scholar
    • Export Citation
  • Bass S, Delmas PD, Pearce G, Hendrich E, Tabensky A & Seeman E 1999 The differing tempo of growth in bone size, mass, and density in girls is region specific. Journal of Clinical Investigation 104 795–804.

    • Search Google Scholar
    • Export Citation
  • Beardsworth LJ, Eyre DR & Dickson IR 1990 Changes with age in the urinary excretion of lysyl- and hydroxylysylpyridinoline, two new markers of bone collagen turnover. Journal of Bone and Mineral Research 5 671–676.

    • Search Google Scholar
    • Export Citation
  • Beaupre GS, Orr TE & Carter DR 1990 An approach for time-dependent bone modeling and remodeling - theoretical development. Journal of Orthopedic Research 8 651–661.

    • Search Google Scholar
    • Export Citation
  • Blimkie CJ, Lefevre J, Beunen GP, Renson R, Dequeker J & Van DP 1993 Fractures, physical activity, and growth velocity in adolescent Belgian boys. Medical Science of Sports and Exercise 25 801–808.

    • Search Google Scholar
    • Export Citation
  • Blumsohn A, Hannon RA, Wrate R, Barton J, AlDehaimi AW, Colwell A & Eastell R 1994 Biochemical markers of bone turnover in girls during puberty. Clinical Endocrinology 40 663–670.

    • Search Google Scholar
    • Export Citation
  • Bollen AM 2000 A prospective longitudinal study of urinary excretion of a bone resorption marker in adolescents. Annals of Human Biology 27 199–211.

    • Search Google Scholar
    • Export Citation
  • Bollen AM & Eyre DR 1994 Bone resorption rates in children monitored by the urinary assay of collagen type I cross-linked peptides. Bone 15 31–34.

    • Search Google Scholar
    • Export Citation
  • Bonjour JP, Carrie AL, Ferrari S, Clavien H, Slosman D, Theintz G & Rizzoli R 1997 Calcium-enriched foods and bone mass growth in prepubertal girls: a randomized, double-blind, placebo-controlled trial. Journal of Clinical Investigation 99 1287–1294.

    • Search Google Scholar
    • Export Citation
  • Cadogan J, Eastell R, Jones N & Barker ME 1997 Milk intake and bone mineral acquisition in adolescent girls: randomised, controlled intervention trial. British Medical Journal 315 1255–1260.

    • Search Google Scholar
    • Export Citation
  • Cadogan J, Blumsohn A, Barker ME & Eastell R 1998 A longitudinal study of bone gain in pubertal girls: anthropometric and biochemical correlates. Journal of Bone and Mineral Research 13 1602–1612.

    • Search Google Scholar
    • Export Citation
  • Cara JF, Rosenfield RL & Furlanetto RW 1987 A longitudinal study of the relationship of plasma somatomedin-C concentration to the pubertal growth spurt. American Journal of Diseases in Childhood 141 562–564.

    • Search Google Scholar
    • Export Citation
  • Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS & Simpson ER 1997 Effect of testosterone and estradiol in a man with aromatase deficiency. New England Journal of Medicine 337 91–95.

    • Search Google Scholar
    • Export Citation
  • Caufriez A 1997 The pubertal spurt: effects of sex steroids on growth hormone and insulin-like growth factor I. European Journal of Obstetrics, Gynecology and Reproductive Biology 71 215–217.

    • Search Google Scholar
    • Export Citation
  • Chan GM, Hoffman K & McMurry M 1995 Effects of dairy products on bone and body composition in pubertal girls. Journal of Pediatrics 126 551–556.

    • Search Google Scholar
    • Export Citation
  • Cole DE, Carpenter TO & Gundberg CM 1985 Serum osteocalcin concentrations in children with metabolic bone disease. Journal of Pediatrics 106 770–776.

    • Search Google Scholar
    • Export Citation
  • Colwell A & Eastell R 1996 The renal clearance of free and conjugated pyridinium cross- links of collagen. Journal of Bone and Mineral Research 11 1976–1980.

    • Search Google Scholar
    • Export Citation
  • Conti A, Ferrero S, Giambona S & Sartorio A 1998 Urinary free deoxypyridinoline levels during childhood. Journal of Endocrinological Investigation 21 318–322.

    • Search Google Scholar
    • Export Citation
  • Costin G, Kaufman FR & Brasel JA 1989 Growth hormone secretory dynamics in subjects with normal stature. Journal of Pediatrics 115 537–544.

    • Search Google Scholar
    • Export Citation
  • Crofton PM, Wade JC, Taylor MR & Holland CV 1997 Serum concentrations of carboxyl-terminal propeptide of type I procollagen, amino-terminal propeptide of type III procollagen, cross-linked carboxyl-terminal telopeptide of type I collagen, and their interrelationships in schoolchildren. Clinical Chemistry 43 1577–1581.

    • Search Google Scholar
    • Export Citation
  • Del RL, Carrascosa A, Pons F, Gusinye M, Yeste D & Domenech FM 1994 Bone mineral density of the lumbar spine in white Mediterranean Spanish children and adolescents: changes related to age, sex, and puberty. Pediatrics Research 35 362–366.

    • Search Google Scholar
    • Export Citation
  • Dibba B, Prentice A, Ceesay M, Stirling DM, Cole TJ & Poskitt EM 2000 Effect of calcium supplementation on bone mineral accretion in Gambian children accustomed to a low-calcium diet. American Journal of Clinical Nutrition 71 544–549.

    • Search Google Scholar
    • Export Citation
  • Eastell R, Simmons PS, Colwell A, Assiri AM, Burritt MF, Russell RG & Riggs BL 1992 Nyctohemeral changes in bone turnover assessed by serum bone Gla-protein concentration and urinary deoxypyridinoline excretion: effects of growth and ageing. Clinical Science 83 375–382.

    • Search Google Scholar
    • Export Citation
  • Fox KM, Magaziner J, Sherwin R, Scott JC, Plato CC, Nevitt M & Cummings S 1993 Reproductive correlates of bone mass in elderly women. Study of Osteoporotic Fractures Research Group. Journal of Bone and Mineral Research 8 901–908.

    • Search Google Scholar
    • Export Citation
  • Fujimoto S, Kubo T, Tanaka H, Miura M & Seino Y 1995 Urinary pyridinoline and deoxypyridinoline in healthy children and in children with growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 80 1922–1928.

    • Search Google Scholar
    • Export Citation
  • Fujiwara S, Kasagi F, Yamada M & Kodama K 1997 Risk factors for hip fracture in a Japanese cohort. Journal of Bone and Mineral Research 12 998–1004.

    • Search Google Scholar
    • Export Citation
  • Garn SM, LaVelle M, Rosenberg KR & Hawthorne VM 1986 Maturational timing as a factor in female fatness and obesity. American Journal of Clinical Nutrition 43 879–883.

    • Search Google Scholar
    • Export Citation
  • Gerdhem P & Obrant KJ 2004 Bone mineral density in old age: the influence of age at menarche and menopause. Journal of Bone and Mineral Metabolism 22 372–375.

    • Search Google Scholar
    • Export Citation
  • Gundberg CM, Lian JB & Gallop PM 1983 Measurements of gamma-carboxyglutamate and circulating osteocalcin in normal children and adults. Clinica Chimica Acta 128 1–8.

    • Search Google Scholar
    • Export Citation
  • Henry YM, Fatayerji D & Eastell R 2004 Attainment of peak bone mass at the lumbar spine, femoral neck and radius in men and women: relative contributions of bone size and volumetric bone mineral density. Osteoporosis International 15 263–273.

    • Search Google Scholar
    • Export Citation
  • Hertel NT, Stoltenberg M, Juul A, Main KM, Muller J, Nielsen CT, Lorenzen IB & Skakkebaek NE 1993 Serum concentrations of Type-I and Type-III procollagen propeptides in healthy children and girls with central precocious puberty during treatment with gonadotropin-releasing hormone analog and cyproterone acetate. Journal of Clinical Endocrinology and Metabolism 76 924–927.

    • Search Google Scholar
    • Export Citation
  • Ho KY, Evans WS, Blizzard RM, Veldhuis JD, Merriam GR, Samojlik E, Furlanetto R, Rogol AD, Kaiser DL & Thorner MO 1987 Effects of sex and age on the 24-h profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. Journal of Clinical Endocrinology 64 51–58.

    • Search Google Scholar
    • Export Citation
  • van Hoof VO, Hoylaerts MF, Geryl H, van Mullem M, Lepoutre LG & De Broe ME 1990 Age and sex distribution of alkaline phosphatase isoenzymes by agarose electrophoresis. Clinical Chemistry 36 875–878.

    • Search Google Scholar
    • Export Citation
  • Ito M, Yamada M, Hayashi K, Ohki M, Uetani M & Nakamura T 1995 Relation of early menarche to high bone mineral density. Calcified Tissue International 57 11–14.

    • Search Google Scholar
    • Export Citation
  • Johansen JS, Giwercman A, Hartwell D, Nielsen CT, Price PA, Christiansen C & Skakkebaek NE 1988 Serum bone Gla-protein as a marker of bone growth in children and adolescents: correlation with age, height, serum insulin-like growth factor I and serum testosterone. Journal of Clinical Endocrinology and Metabolism 67 273–278.

    • Search Google Scholar
    • Export Citation
  • Johnston CC, Miller JZ, Slemenda CW, Reister TK, Hui S, Christian JC & Peacock M 1992 Calcium supplementation and increases in bone mineral density in children. New England Journal of Medicine 327 82–87.

    • Search Google Scholar
    • Export Citation
  • Jones IE, Taylor RW, Williams SM, Manning PJ & Goulding A 2002a Four-year gain in bone mineral in girls with and without past forearm fractures: a DXA study. Dual energy X-ray absorptiometry. Journal of Bone and Mineral Research 17 1065–1072.

    • Search Google Scholar
    • Export Citation
  • Jones IE, Williams SM, Dow N & Goulding A 2002b How many children remain fracture-free during growth? A longitudinal study of children and adolescents participating in the Dunedin Multidisciplinary Health and Development Study. Osteoporosis International 13 990–995.

    • Search Google Scholar
    • Export Citation
  • Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, Muller J, Hall K & Skakkebaek NE 1994 Serum insulin-like growth factor I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size and body mass index. Journal of Clinical Endocrinology and Metabolism 78 744–752.

    • Search Google Scholar
    • Export Citation
  • Kannus P, Haapasalo H, Sankelo M, Sievanen H, Pasanen M, Heinonen A, Oja P & Vuori I 1995 Effect of starting age of physical activity on bone mass in the dominant arm of tennis and squash players. Annals of Internal Medicine 123 27–31.

    • Search Google Scholar
    • Export Citation
  • Kanzaki S, Hosoda K, Moriwake T, Tanaka H, Kubo T, Inoue M, Higuchi J, Yamaji T & Seino Y 1992 Serum propeptide and intact molecular osteocalcin in normal children and children with growth hormone (GH) deficiency - a potential marker of bone growth and response to GH therapy. Journal of Clinical Endocrinology and Metabolism 75 1104–1109.

    • Search Google Scholar
    • Export Citation
  • Khosla S, Melton LJ III, Atkinson EJ, O’Fallon WM, Klee GG & Riggs BL 1998 Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. Journal of Clinical Endocrinology and Metabolism 83 2266–2274.

    • Search Google Scholar
    • Export Citation
  • Khosla S, Melton LJ III, Dekutoski MB, Achenbach SJ, Oberg AL & Riggs BL 2003 Incidence of childhood distal forearm fractures over 30 years: a population-based study. Journal of the American Medical Association 290 1479–1485.

    • Search Google Scholar
    • Export Citation
  • Kikuchi T, Hashimoto N, Kawasaki T, Kataoka S, Takahashi H & Uchiyama M 1998 Plasma levels of carboxy terminal propeptide of type I procollagen and pyridinoline cross-linked telopeptide of type I collagen in healthy school children. Acta Paediatrica 87 825–829.

    • Search Google Scholar
    • Export Citation
  • Kubo T, Tanaka H, Inoue M, Kanzaki S & Seino Y 1995 Serum levels of carboxyterminal propeptide of type I procollagen and pyridinoline crosslinked telopeptide of type I collagen in normal children and children with growth hormone (GH) deficiency during GH therapy. Bone 17 397–401.

    • Search Google Scholar
    • Export Citation
  • Kusec V, Virdi AS, Prince R & Triffitt JT 1998 Localization of estrogen receptor-alpha in human and rabbit skeletal tissues. Journal of Clinical Endocrinology and Metabolism 83 2421–2428.

    • Search Google Scholar
    • Export Citation
  • Lanyon L, Armstrong V, Ong D, Zaman G & Price J 2004 Is estrogen receptor alpha key to controlling bones’ resistance to fracture? Journal of Endocrinology 182 183–191.

    • Search Google Scholar
    • Export Citation
  • Lee WTK, Leung SSF, Wang SH, Xu YC, Zeng WP, Lau J, Oppenheimer SJ & Cheng JCY 1994 Double-blind controlled calcium supplementation and bone mineral accretion in children accustomed to a low-calcium diet. American Journal of Clinical Nutrition 60 744–750.

    • Search Google Scholar
    • Export Citation
  • Libanati C, Baylink DJ, Lois-Wenzel E, Srinvasan N & Mohan S 1999 Studies on the potential mediators of skeletal changes occurring during puberty in girls. Journal of Clinical Endocrinology and Metabolism 84 2807–2814.

    • Search Google Scholar
    • Export Citation
  • Lloyd T, Andon MB, Rollings N, Martel JK, Landis JR, Demers LM, Eggli DF, Kieselhorst K & Kulin HE 1993 Calcium supplementation and bone mineral density in adolescent girls. Journal of the American Medical Association 270 841–844.

    • Search Google Scholar
    • Export Citation
  • Luna AM, Wilson DM, Wibbelsman CJ, Brown RC, Nagashima RJ, Hintz RL & Rosenfeld RG 1983 Somatomedins in adolescence: a cross-sectional study of the effect of puberty on plasma insulin-like growth factor I and II levels. Journal of Clinical Endocrinology and Metabolism 57 268–271.

    • Search Google Scholar
    • Export Citation
  • Ma D & Jones G 2003 The association between bone mineral density, metacarpal morphometry, and upper limb fractures in children: a population-based case-control study. Journal of Clinical Endocrinology and Metabolism 88 1486–1491.

    • Search Google Scholar
    • Export Citation
  • Magarey AM, Boulton TJ, Chatterton BE, Schultz C, Nordin BE & Cockington RA 1999 Bone growth from 11 to 17 years: relationship to growth, gender and changes with pubertal status including timing of menarche. Acta Paediatrica 88 139–146.

    • Search Google Scholar
    • Export Citation
  • Magnusson P, Hager A & Larsson L 1995 Serum osteocalcin and bone and liver alkaline phosphatase isoforms in healthy children and adolescents. Pediatrics Research 38 955–961.

    • Search Google Scholar
    • Export Citation
  • Magnusson P, Larsson L, Magnusson M, Davie MW & Sharp CA 1999 Isoforms of bone alkaline phosphatase: characterization and origin in human trabecular and cortical bone. Journal of Bone and Mineral Research 14 1926–1933.

    • Search Google Scholar
    • Export Citation
  • Marowska J, Kobylinska M, Lukaszkiewicz J, Talajko A, Rymkiewicz-Kluczynska B & Lorenc RS 1996 Pyridinium crosslinks of collagen as a marker of bone resorption rates in children and adolescents: normal values and clinical application. Bone 19 669–677.

    • Search Google Scholar
    • Export Citation
  • Matkovic V 1996 Skeletal development and bone turnover revisited. Journal of Clinical Endocrinology and Metabolism 81 2013–2016.

  • Matkovic V, Ilich JZ, Skugor M, Badenhop NE, Goel P, Clairmont A, Klisovic D, Nahhas RW & Landoll JD 1997 Leptin is inversely related to age at menarche in human females. Journal of Clinical Endocrinology and Metabolism 82 3239–3245.

    • Search Google Scholar
    • Export Citation
  • van der Meulen MC, Carter DR & Beaupre GS 2001 Skeletal development: mechanical consequences of growth, aging, and disease. In Osteoporosis, edn 2nd, pp 471–488. Eds R Marcus, D Feldman & JL Kelsey. San Diego: Academic Press.

  • Meyer HE, Falch JA, O’Neill T, Tverdal A & Varlow J 1995 Height and body mass index in Oslo, Norway, compared with other regions of Europe: do they explain differences in the incidence of hip fracture? European Vertebral Osteoporosis Study Group. Bone 17 347–350.

    • Search Google Scholar
    • Export Citation
  • Mora S, Prinster C, Proverbio MC, Bellini A, de Poli SC, Weber G, Abbiati G & Chiumello G 1998 Urinary markers of bone turnover in healthy children and adolescents: age-related changes and effect of puberty. Calcified Tissue International 63 369–374.

    • Search Google Scholar
    • Export Citation
  • Mora S, Pitukcheewanont P, Kaufman FR, Nelson JC & Gilsanz V 1999 Biochemical markers of bone turnover and the volume and the density of bone in children at different stages of sexual development. Journal of Bone and Mineral Research 14 1664–1671.

    • Search Google Scholar
    • Export Citation
  • Moreira-Andres MN, Papapietro K, Canizo FJ, Rejas J, Larrodera L & Hawkins FG 1995 Correlations between bone mineral density, insulin-like growth factor I and auxological variables. European Journal of Endocrinology 132 573–579.

    • Search Google Scholar
    • Export Citation
  • Morishima A, Grumbach MM, Simpson ER, Fisher C & Qin K 1995 Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. Journal of Clinical Endocrinology and Metabolism 80 3689–3698.

    • Search Google Scholar
    • Export Citation
  • Nilsson LO, Boman A, Savendahl L, Grigelioniene G, Ohlsson C, Ritzen EM & Wroblewski J 1999 Demonstration of estrogen receptor-beta immunoreactivity in human growth plate cartilage. Journal of Clinical Endocrinology and Metabolism 84 370–373.

    • Search Google Scholar
    • Export Citation
  • Ninomiya JT, Tracy RP, Calore JD, Gendreau MA, Kelm RJ & Mann KG 1990 Heterogeneity of human bone. Journal of Bone and Mineral Research 5 933–938.

    • Search Google Scholar
    • Export Citation
  • Ohishi T, Takahashi M, Kawana K, Aoshima H, Hoshino H, Horiuchi K, Kushida K & Inoue T 1993 Age-related changes of urinary pyridinoline and deoxypyridinoline in Japanese subjects. Clinical and Investigative Medicine 16 319–325.

    • Search Google Scholar
    • Export Citation
  • Parfitt AM 1994 The two faces of growth: benefits and risks to bone integrity. Osteoporosis International 4 382–398.

  • Parfitt AM 2002 Misconceptions (1): epiphyseal fusion causes cessation of growth. Bone 30 337–339.

  • Parfitt AM, Travers R, Rauch F & Glorieux FH 2000 Structural and cellular changes during bone growth in healthy children. Bone 27 487–494.

    • Search Google Scholar
    • Export Citation
  • Pasco JA, Panahi S, Henry MJ, Seeman E, Nicholson GC & Kotowicz MA 1999 Femoral neck dimensions are unlikely to be associated with age at menarche. Osteoporosis International 9 557–559.

    • Search Google Scholar
    • Export Citation
  • Pfeilschifter J, Scheidt-Nave C, Leidig-Bruckner G, Woitge HW, Blum WF, Wuster C, Haack D & Ziegler R 1996 Relationship between circulating insulin-like growth factor components and sex hormones in a population-based sample of 50- to 80-year-old men and women. Journal of Clinical Endocrinology and Metabolism 81 2534–2540.

    • Search Google Scholar
    • Export Citation
  • Rauch F, Schnabel D, Seibel MJ, Remer T, Stabrey A, Michalk D & Schonau E 1995 Urinary excretion of galactosyl-hydroxylysine is a marker of growth in children. Journal of Clinical Endocrinology and Metabolism 80 1295–1300.

    • Search Google Scholar
    • Export Citation
  • Rauch F, Rauch R, Woitge HW, Seibel MJ & Schonau E 1996 Urinary immunoreactive deoxypyridinoline in children and adolescents: variations with age, sex and growth velocity. Scandinavian Journal of Clinical and Laboratory Investigation 56 715–719.

    • Search Google Scholar
    • Export Citation
  • Rauch F, Klein K, Allolio B & Schonau E 1999 Age at menarche and cortical bone geometry in premenopausal women. Bone 25 69–73.

  • Riggs BL, Khosla S & Melton LJ III 2002 Sex steroids and the construction and conservation of the adult skeleton. Endocrine Reviews 23 279–302.

    • Search Google Scholar
    • Export Citation
  • Riis BJ, Krabbe S, Christiansen C, Catherwood BD & Deftos LJ 1985 Bone turnover in male puberty: a longitudinal study. Calcified Tissue International 37 213–217.

    • Search Google Scholar
    • Export Citation
  • Rosenthal DI, Mayo-Smith W, Hayes CW, Khurana JS, Biller BM, Neer RM & Klibanski A 1989 Age and bone mass in premenopausal women. Journal of Bone and Mineral Research 4 533–538.

    • Search Google Scholar
    • Export Citation
  • Ross JL, Cassorla FG, Skerda MC, Valk IM, Loriaux DL & Cutler GB Jr 1983 A preliminary study of the effect of estrogen dose on growth in Turner’s syndrome. New England Journal of Medicine 309 1104–1106.

    • Search Google Scholar
    • Export Citation
  • Rotteveel J, Schoute E & Delemarre-Van de Waal HA 1997 Serum procollagen I carboxyterminal propeptide (PICP) levels through puberty: relation to height velocity and serum hormone levels. Acta Paediatrica 86 143–147.

    • Search Google Scholar
    • Export Citation
  • Roy DK, O’Neill TW, Finn JD, Lunt M, Silman AJ, Felsenberg D, Armbrecht G, Banzer D, Benevolenskaya LI, Bhalla A, Bruges AJ, Cannata JB, Cooper C, Dequeker J, Diaz MN, Eastell R, Yershova OB, Felsch B, Gowin W, Havelka S, Hoszowski K, Ismail AA, Jajic I, Janott I, Johnell O, Kanis JA, Kragl G, Lopez VA, Lorenc R, Lyritis G, Masaryk P, Matthis C, Miazgowski T, Gennari C, Pols HA, Poor G, Raspe HH, Reid DM, Reisinger W, Scheidt-Nave C, Stepan JJ, Todd CJ, Weber K, Woolf AD & Reeve J 2003 Determinants of incident vertebral fracture in men and women: results from the European Prospective Osteoporosis Study (EPOS). Osteoporosis International 14 19–26.

    • Search Google Scholar
    • Export Citation
  • Rozen GS, Rennert G, Dodiuk-Gad RP, Rennert HS, Ish-Shalom N, Diab G, Raz B & Ish-Shalom S 2003 Calcium supplementation provides an extended window of opportunity for bone mass accretion after menarche. American Journal of Clinical Nutrition 78 993–998.

    • Search Google Scholar
    • Export Citation
  • Sabatier JP, Guaydier-Souquieres G, Laroche D, Benmalek A, Fournier L, Guillon-Metz F, Delavenne J & Denis AY 1996 Bone mineral acquisition during adolescence and early adulthood: a study in 574 healthy females 10–24 years of age. Osteoporosis International 6 141–148.

    • Search Google Scholar
    • Export Citation
  • Schiele F, Henny J, Hitz J, Petitclerc C, Guenguen R & Siest G 1983 Total bone and liver alkaline phosphatases in plasma: biological variations and reference limits. Clinical Chemistry 29 634–641.

    • Search Google Scholar
    • Export Citation
  • Sen AT, Derman O & Kinik E 2000 The relationship between osteocalcin levels and sexual stages of puberty in male children. Turkish Journal of Pediatrics 42 281–285.

    • Search Google Scholar
    • Export Citation
  • Shaw NJ & Bishop NJ 1995 Mineral accretion in growing bones - a framework for the future? Archives of Diseases in Childhood 72 177–179.

  • Silbergeld A, Litwin A, Bruchis S, Varsano I & Laron Z 1986 Insulin-like growth factor I (IGF-I) in healthy children, adolescents and adults as determined by a radioimmunoassay specific for the synthetic 53–70 peptide region. Clinical Endocrinology 25 67–74.

    • Search Google Scholar
    • Export Citation
  • Silman AJ 2003 Risk factors for Colles’ fracture in men and women: results from the European Prospective Osteoporosis Study. Osteoporosis International 14 213–218.

    • Search Google Scholar
    • Export Citation
  • Slemenda CW, Reister TK, Hui SL, Miller JZ, Christian JC & Johnston CC Jr 1994 Influences on skeletal mineralization in children and adolescents: evidence for varying effects of sexual maturation and physical activity. Journal of Pediatrics 125 201–207.

    • Search Google Scholar
    • Export Citation
  • Slemenda CW, Peacock M, Hui S, Zhou L & Johnston CC 1997 Reduced rates of skeletal remodeling are associated with increased bone mineral density during the development of peak skeletal mass. Journal of Bone and Mineral Research 12 676–682.

    • Search Google Scholar
    • Export Citation
  • Smedsrod B, Melkko J, Risteli L & Risteli J 1990 Circulating C-terminal propeptide of type I procollagen is cleared mainly via the mannose receptor in liver endothelial cells. Biochemical Journal 271 345–350.

    • Search Google Scholar
    • Export Citation
  • Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB & Korach KS 1994 Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man [see comments] [published erratum appears in New England Journal of Medicine 1995 332 131]. New England Journal of Medicine 331 1056–1061.

    • Search Google Scholar
    • Export Citation
  • Sorva R, Anttila R, Siimes MA, Sorva A, Tahtela R & Turpeinen M 1997 Serum markers of collagen metabolism and serum osteocalcin in relation to pubertal development in 57 boys at 14 years of age. Pediatrics Research 42 528–532.

    • Search Google Scholar
    • Export Citation
  • Stanhope R, Preece MA, Grant DB & Brook CG 1988 New concepts of the growth spurt of puberty. Acta Paediatrica Scandinavica Supplement 347 30–37.

    • Search Google Scholar
    • Export Citation
  • Stear SJ, Prentice A, Jones SC & Cole TJ 2003 Effect of a calcium and exercise intervention on the bone mineral status of 16- to 18-year-old adolescent girls. American Journal of Clinical Nutrition 77 985–992.

    • Search Google Scholar
    • Export Citation
  • Szulc P, Seeman E & Delmas PD 2000 Biochemical measurements of bone turnover in children and adolescents. Osteoporosis International 11 281–294.

    • Search Google Scholar
    • Export Citation
  • Tanner JM 1975 Growth and endocrinology of the adolescence. In Endocrine and Genetic Diseases of Childhood and Adolescence, pp 14–64. Ed LI Gardner. Philadelphia: WB Saunders Company.

  • Theintz G, Buchs B, Rizzoli R, Slosman D, Clavien H, Sizonenko PC & Bonjour JP 1992 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. Journal of Clinical Endocrinology and Metabolism 75 1060–1065.

    • Search Google Scholar
    • Export Citation
  • Tobias JH & Compston JE 1999 Does estrogen stimulate osteoblast function in postmenopausal women? Bone 24 121–124.

  • Tobiume H, Kanzaki S, Hida S, Ono T, Moriwake T, Yamauchi S, Tanaka H & Seino Y 1997 Serum bone alkaline phosphatase isoenzyme levels in normal children and children with growth hormone (GH) deficiency: a potential marker for bone formation and response to GH therapy. Journal of Clinical Endocrinology and Metabolism 82 2056–2061.

    • Search Google Scholar
    • Export Citation
  • Tommasi M, Bacciottini L, Benucci A, Brocchi A, Passeri A, Saracini D, D’Agata A & Cappelli G 1996 Serum biochemical markers of bone turnover in healthy infants and children. International Journal of Biological Markers 11 159–164.

    • Search Google Scholar
    • Export Citation
  • Trivedi P, Risteli J, Risteli L, Hindmarsh PC, Brook CGD & Mowat AP 1991 Serum concentrations of the Type-I and Type-III procollagen propeptides as biochemical markers of growth velocity in healthy infants and children and in children with growth disorders. Pediatrics Research 30 276–280.

    • Search Google Scholar
    • Export Citation
  • Tuckermann JP, Pittois K, Partridge NC, Merregaert J & Angel P 2000 Collagenase-3 (MMP-13) and integral membrane protein 2a (Itm2a) are marker genes of chondrogenic/osteoblastic cells in bone formation: sequential temporal, and spatial expression of Itm2a, alkaline phosphatase, MMP-13, and osteocalcin in the mouse. Journal of Bone and Mineral Research 15 1257–1265.

    • Search Google Scholar
    • Export Citation
  • Varenna M, Binelli L, Zucchi F, Ghiringhelli D, Gallazzi M & Sinigaglia L 1999 Prevalence of osteoporosis by educational level in a cohort of postmenopausal women. Osteoporosis International 9 236–241.

    • Search Google Scholar
    • Export Citation
  • Veldhuis JD, Anderson SM, Patrie JT & Bowers CY 2004 Estradiol supplementation in postmenopausal women doubles rebound-like release of growth hormone (GH) triggered by sequential infusion and withdrawal of somatostatin: evidence that estrogen facilitates endogenous GH-releasing hormone drive. Journal of Clinical Endocrinology and Metabolism 89 121–127.

    • Search Google Scholar
    • Export Citation
  • Vihko R & Apter D 1984 Endocrine characteristics of adolescent menstrual cycles: impact of early menarche. Journal of Steroid Biochemistry 20 231–236.

    • Search Google Scholar
    • Export Citation
  • Weaver CM, Peacock M, Martin BR, McCabe GP, Zhao J, Smith DL & Wastney ME 1997 Quantification of biochemical markers of bone turnover by kinetic measures of bone formation and resorption in young healthy females. Journal of Bone and Mineral Research 12 1714–1720.

    • Search Google Scholar
    • Export Citation
  • Weise M, De-Levi S, Barnes KM, Gafni RI, Abad V & Baron J 2001 Effects of estrogen on growth plate senescence and epiphyseal fusion. PNAS 98 6871–6876.

    • Search Google Scholar
    • Export Citation

 

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    Bone turnover is higher during childhood than adulthood. Note the very high levels of bone remodelling during infancy, and how bone turnover decreases rapidly after puberty, using (A) bone histomorphometry, bone formation rate with bone volume referent (BFR/BV), and (B) the urinary bone resorption marker, NTX. BCE, bone collagen equivalents; Curved lines, best-fitting fifth order polynomial; Straight line, simple linear regression line. Reproduced from Parfitt et al.(2000) with permission from Elsevier and from Mora et al.(1998) with permission from Springer-Verlag.

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    Biochemical markers of bone formation (shaded boxes) and resorption (open boxes) in mid-puberty (Tanner stages II and III) in girls relative to the mean level in adults. ALP, alkaline phosphatase; i, immunoreactive; w, wheat germ lectin; ICTP, type I collagen C-telopeptide; uGal-Hyl/Cr, urinary galactosyl hydroxylysine to creatine ratio. Data from Blumsohn et al.(1994).

  • View in gallery View in gallery View in gallery

    The increase in serum oestradiol levels precede menarche and are associated with a slowing of growth velocity and a decrease in bone turnover markers. Note how the IGF-I levels continue to increase, despite the deceleration in height velocity. The maximum gain in bone mineral content occurs at menarche and subsequently serum PTH levels decline. (A) Change (Δ) in height (a), total body bone mineral content (TBBMC) (b) and bone mineral density (TBBMD) (c). (B) Levels of and change in serum bone ALP (immunoreactive (i)BAP) (a and b) and urinary free DPD (iFDpd) (c and d). (C) Levels of and change in serum parathyroid hormone (PTH) (a and b), oestradiol (E2) (c and d), and insulin-like growth factor I (IGF-I) (e and f) in healthy girls entering the study at ages 11 to 12 years, with 18 months of follow-up. Reproduced from Cadogan et al.(1998) with permission from the American Society for Bone and Mineral Research.

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    Fractures are common at the onset of puberty in boys and girls; they most commonly involve the distal forearm, as shown here. Reproduced from Khosla et al.(2003) with permission from the American Medical Association.

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    Two models for the mechanism underlying the association between early menarche and low risk of fracture. Model 2 shows the duration of reproductive life in a woman with early menarche and one with late menarche (and a period of anovulatory, irregular cycles). In this case, the woman with late menarche would have less lifetime exposure to oestrogen. However, fracture risk is greater in the woman with few reproductive years due to later menarche (b) than in the woman with few reproductive years due to early menopause (c).

  • Argente J, Barrios V, Pozo J, Munoz MT, Hervas F, Stene M & Hernandez M 1993 Normative data for insulin-like growth factors (IGFs), IGF-binding proteins, and growth hormone-binding protein in a healthy Spanish pediatric population: age- and sex-related changes. Journal of Clinical Endocrinology and Metabolism 77 1522–1528.

    • Search Google Scholar
    • Export Citation
  • Bailey DA, Wedge JH, McCulloch RG, Martin AD & Bernhardson SC 1989 Epidemiology of fractures of the distal end of the radius in children as associated with growth. Journal of Bone and Joint Surgery of America 71 1225–1231.

    • Search Google Scholar
    • Export Citation
  • Bailey DA, Mckay HA, Mirwald RL, Crocker PR & Faulkner RA 1999 A six-year longitudinal study of the relationship of physical activity to bone mineral accrual in growing children: the university of Saskatchewan bone mineral accrual study. Journal of Bone and Mineral Research 14 1672–1679.

    • Search Google Scholar
    • Export Citation
  • Bass S, Delmas PD, Pearce G, Hendrich E, Tabensky A & Seeman E 1999 The differing tempo of growth in bone size, mass, and density in girls is region specific. Journal of Clinical Investigation 104 795–804.

    • Search Google Scholar
    • Export Citation
  • Beardsworth LJ, Eyre DR & Dickson IR 1990 Changes with age in the urinary excretion of lysyl- and hydroxylysylpyridinoline, two new markers of bone collagen turnover. Journal of Bone and Mineral Research 5 671–676.

    • Search Google Scholar
    • Export Citation
  • Beaupre GS, Orr TE & Carter DR 1990 An approach for time-dependent bone modeling and remodeling - theoretical development. Journal of Orthopedic Research 8 651–661.

    • Search Google Scholar
    • Export Citation
  • Blimkie CJ, Lefevre J, Beunen GP, Renson R, Dequeker J & Van DP 1993 Fractures, physical activity, and growth velocity in adolescent Belgian boys. Medical Science of Sports and Exercise 25 801–808.

    • Search Google Scholar
    • Export Citation
  • Blumsohn A, Hannon RA, Wrate R, Barton J, AlDehaimi AW, Colwell A & Eastell R 1994 Biochemical markers of bone turnover in girls during puberty. Clinical Endocrinology 40 663–670.

    • Search Google Scholar
    • Export Citation
  • Bollen AM 2000 A prospective longitudinal study of urinary excretion of a bone resorption marker in adolescents. Annals of Human Biology 27 199–211.

    • Search Google Scholar
    • Export Citation
  • Bollen AM & Eyre DR 1994 Bone resorption rates in children monitored by the urinary assay of collagen type I cross-linked peptides. Bone 15 31–34.

    • Search Google Scholar
    • Export Citation
  • Bonjour JP, Carrie AL, Ferrari S, Clavien H, Slosman D, Theintz G & Rizzoli R 1997 Calcium-enriched foods and bone mass growth in prepubertal girls: a randomized, double-blind, placebo-controlled trial. Journal of Clinical Investigation 99 1287–1294.

    • Search Google Scholar
    • Export Citation
  • Cadogan J, Eastell R, Jones N & Barker ME 1997 Milk intake and bone mineral acquisition in adolescent girls: randomised, controlled intervention trial. British Medical Journal 315 1255–1260.

    • Search Google Scholar
    • Export Citation
  • Cadogan J, Blumsohn A, Barker ME & Eastell R 1998 A longitudinal study of bone gain in pubertal girls: anthropometric and biochemical correlates. Journal of Bone and Mineral Research 13 1602–1612.

    • Search Google Scholar
    • Export Citation
  • Cara JF, Rosenfield RL & Furlanetto RW 1987 A longitudinal study of the relationship of plasma somatomedin-C concentration to the pubertal growth spurt. American Journal of Diseases in Childhood 141 562–564.

    • Search Google Scholar
    • Export Citation
  • Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS & Simpson ER 1997 Effect of testosterone and estradiol in a man with aromatase deficiency. New England Journal of Medicine 337 91–95.

    • Search Google Scholar
    • Export Citation
  • Caufriez A 1997 The pubertal spurt: effects of sex steroids on growth hormone and insulin-like growth factor I. European Journal of Obstetrics, Gynecology and Reproductive Biology 71 215–217.

    • Search Google Scholar
    • Export Citation
  • Chan GM, Hoffman K & McMurry M 1995 Effects of dairy products on bone and body composition in pubertal girls. Journal of Pediatrics 126 551–556.

    • Search Google Scholar
    • Export Citation
  • Cole DE, Carpenter TO & Gundberg CM 1985 Serum osteocalcin concentrations in children with metabolic bone disease. Journal of Pediatrics 106 770–776.

    • Search Google Scholar
    • Export Citation
  • Colwell A & Eastell R 1996 The renal clearance of free and conjugated pyridinium cross- links of collagen. Journal of Bone and Mineral Research 11 1976–1980.

    • Search Google Scholar
    • Export Citation
  • Conti A, Ferrero S, Giambona S & Sartorio A 1998 Urinary free deoxypyridinoline levels during childhood. Journal of Endocrinological Investigation 21 318–322.

    • Search Google Scholar
    • Export Citation
  • Costin G, Kaufman FR & Brasel JA 1989 Growth hormone secretory dynamics in subjects with normal stature. Journal of Pediatrics 115 537–544.

    • Search Google Scholar
    • Export Citation
  • Crofton PM, Wade JC, Taylor MR & Holland CV 1997 Serum concentrations of carboxyl-terminal propeptide of type I procollagen, amino-terminal propeptide of type III procollagen, cross-linked carboxyl-terminal telopeptide of type I collagen, and their interrelationships in schoolchildren. Clinical Chemistry 43 1577–1581.

    • Search Google Scholar
    • Export Citation
  • Del RL, Carrascosa A, Pons F, Gusinye M, Yeste D & Domenech FM 1994 Bone mineral density of the lumbar spine in white Mediterranean Spanish children and adolescents: changes related to age, sex, and puberty. Pediatrics Research 35 362–366.

    • Search Google Scholar
    • Export Citation
  • Dibba B, Prentice A, Ceesay M, Stirling DM, Cole TJ & Poskitt EM 2000 Effect of calcium supplementation on bone mineral accretion in Gambian children accustomed to a low-calcium diet. American Journal of Clinical Nutrition 71 544–549.

    • Search Google Scholar
    • Export Citation
  • Eastell R, Simmons PS, Colwell A, Assiri AM, Burritt MF, Russell RG & Riggs BL 1992 Nyctohemeral changes in bone turnover assessed by serum bone Gla-protein concentration and urinary deoxypyridinoline excretion: effects of growth and ageing. Clinical Science 83 375–382.

    • Search Google Scholar
    • Export Citation
  • Fox KM, Magaziner J, Sherwin R, Scott JC, Plato CC, Nevitt M & Cummings S 1993 Reproductive correlates of bone mass in elderly women. Study of Osteoporotic Fractures Research Group. Journal of Bone and Mineral Research 8 901–908.

    • Search Google Scholar
    • Export Citation
  • Fujimoto S, Kubo T, Tanaka H, Miura M & Seino Y 1995 Urinary pyridinoline and deoxypyridinoline in healthy children and in children with growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism 80 1922–1928.

    • Search Google Scholar
    • Export Citation
  • Fujiwara S, Kasagi F, Yamada M & Kodama K 1997 Risk factors for hip fracture in a Japanese cohort. Journal of Bone and Mineral Research 12 998–1004.

    • Search Google Scholar
    • Export Citation
  • Garn SM, LaVelle M, Rosenberg KR & Hawthorne VM 1986 Maturational timing as a factor in female fatness and obesity. American Journal of Clinical Nutrition 43 879–883.

    • Search Google Scholar
    • Export Citation
  • Gerdhem P & Obrant KJ 2004 Bone mineral density in old age: the influence of age at menarche and menopause. Journal of Bone and Mineral Metabolism 22 372–375.

    • Search Google Scholar
    • Export Citation
  • Gundberg CM, Lian JB & Gallop PM 1983 Measurements of gamma-carboxyglutamate and circulating osteocalcin in normal children and adults. Clinica Chimica Acta 128 1–8.

    • Search Google Scholar
    • Export Citation
  • Henry YM, Fatayerji D & Eastell R 2004 Attainment of peak bone mass at the lumbar spine, femoral neck and radius in men and women: relative contributions of bone size and volumetric bone mineral density. Osteoporosis International 15 263–273.

    • Search Google Scholar
    • Export Citation
  • Hertel NT, Stoltenberg M, Juul A, Main KM, Muller J, Nielsen CT, Lorenzen IB & Skakkebaek NE 1993 Serum concentrations of Type-I and Type-III procollagen propeptides in healthy children and girls with central precocious puberty during treatment with gonadotropin-releasing hormone analog and cyproterone acetate. Journal of Clinical Endocrinology and Metabolism 76 924–927.

    • Search Google Scholar
    • Export Citation
  • Ho KY, Evans WS, Blizzard RM, Veldhuis JD, Merriam GR, Samojlik E, Furlanetto R, Rogol AD, Kaiser DL & Thorner MO 1987 Effects of sex and age on the 24-h profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. Journal of Clinical Endocrinology 64 51–58.

    • Search Google Scholar
    • Export Citation
  • van Hoof VO, Hoylaerts MF, Geryl H, van Mullem M, Lepoutre LG & De Broe ME 1990 Age and sex distribution of alkaline phosphatase isoenzymes by agarose electrophoresis. Clinical Chemistry 36 875–878.

    • Search Google Scholar
    • Export Citation
  • Ito M, Yamada M, Hayashi K, Ohki M, Uetani M & Nakamura T 1995 Relation of early menarche to high bone mineral density. Calcified Tissue International 57 11–14.

    • Search Google Scholar
    • Export Citation
  • Johansen JS, Giwercman A, Hartwell D, Nielsen CT, Price PA, Christiansen C & Skakkebaek NE 1988 Serum bone Gla-protein as a marker of bone growth in children and adolescents: correlation with age, height, serum insulin-like growth factor I and serum testosterone. Journal of Clinical Endocrinology and Metabolism 67 273–278.

    • Search Google Scholar
    • Export Citation
  • Johnston CC, Miller JZ, Slemenda CW, Reister TK, Hui S, Christian JC & Peacock M 1992 Calcium supplementation and increases in bone mineral density in children. New England Journal of Medicine 327 82–87.

    • Search Google Scholar
    • Export Citation
  • Jones IE, Taylor RW, Williams SM, Manning PJ & Goulding A 2002a Four-year gain in bone mineral in girls with and without past forearm fractures: a DXA study. Dual energy X-ray absorptiometry. Journal of Bone and Mineral Research 17 1065–1072.

    • Search Google Scholar
    • Export Citation
  • Jones IE, Williams SM, Dow N & Goulding A 2002b How many children remain fracture-free during growth? A longitudinal study of children and adolescents participating in the Dunedin Multidisciplinary Health and Development Study. Osteoporosis International 13 990–995.

    • Search Google Scholar
    • Export Citation
  • Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, Muller J, Hall K & Skakkebaek NE 1994 Serum insulin-like growth factor I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size and body mass index. Journal of Clinical Endocrinology and Metabolism 78 744–752.

    • Search Google Scholar
    • Export Citation
  • Kannus P, Haapasalo H, Sankelo M, Sievanen H, Pasanen M, Heinonen A, Oja P & Vuori I 1995 Effect of starting age of physical activity on bone mass in the dominant arm of tennis and squash players. Annals of Internal Medicine 123 27–31.

    • Search Google Scholar
    • Export Citation
  • Kanzaki S, Hosoda K, Moriwake T, Tanaka H, Kubo T, Inoue M, Higuchi J, Yamaji T & Seino Y 1992 Serum propeptide and intact molecular osteocalcin in normal children and children with growth hormone (GH) deficiency - a potential marker of bone growth and response to GH therapy. Journal of Clinical Endocrinology and Metabolism 75 1104–1109.

    • Search Google Scholar
    • Export Citation
  • Khosla S, Melton LJ III, Atkinson EJ, O’Fallon WM, Klee GG & Riggs BL 1998 Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. Journal of Clinical Endocrinology and Metabolism 83 2266–2274.

    • Search Google Scholar
    • Export Citation
  • Khosla S, Melton LJ III, Dekutoski MB, Achenbach SJ, Oberg AL & Riggs BL 2003 Incidence of childhood distal forearm fractures over 30 years: a population-based study. Journal of the American Medical Association 290 1479–1485.

    • Search Google Scholar
    • Export Citation
  • Kikuchi T, Hashimoto N, Kawasaki T, Kataoka S, Takahashi H & Uchiyama M 1998 Plasma levels of carboxy terminal propeptide of type I procollagen and pyridinoline cross-linked telopeptide of type I collagen in healthy school children. Acta Paediatrica 87 825–829.

    • Search Google Scholar
    • Export Citation
  • Kubo T, Tanaka H, Inoue M, Kanzaki S & Seino Y 1995 Serum levels of carboxyterminal propeptide of type I procollagen and pyridinoline crosslinked telopeptide of type I collagen in normal children and children with growth hormone (GH) deficiency during GH therapy. Bone 17 397–401.

    • Search Google Scholar
    • Export Citation
  • Kusec V, Virdi AS, Prince R & Triffitt JT 1998 Localization of estrogen receptor-alpha in human and rabbit skeletal tissues. Journal of Clinical Endocrinology and Metabolism 83 2421–2428.

    • Search Google Scholar
    • Export Citation
  • Lanyon L, Armstrong V, Ong D, Zaman G & Price J 2004 Is estrogen receptor alpha key to controlling bones’ resistance to fracture? Journal of Endocrinology 182 183–191.

    • Search Google Scholar
    • Export Citation
  • Lee WTK, Leung SSF, Wang SH, Xu YC, Zeng WP, Lau J, Oppenheimer SJ & Cheng JCY 1994 Double-blind controlled calcium supplementation and bone mineral accretion in children accustomed to a low-calcium diet. American Journal of Clinical Nutrition 60 744–750.

    • Search Google Scholar
    • Export Citation
  • Libanati C, Baylink DJ, Lois-Wenzel E, Srinvasan N & Mohan S 1999 Studies on the potential mediators of skeletal changes occurring during puberty in girls. Journal of Clinical Endocrinology and Metabolism 84 2807–2814.

    • Search Google Scholar
    • Export Citation
  • Lloyd T, Andon MB, Rollings N, Martel JK, Landis JR, Demers LM, Eggli DF, Kieselhorst K & Kulin HE 1993 Calcium supplementation and bone mineral density in adolescent girls. Journal of the American Medical Association 270 841–844.

    • Search Google Scholar
    • Export Citation
  • Luna AM, Wilson DM, Wibbelsman CJ, Brown RC, Nagashima RJ, Hintz RL & Rosenfeld RG 1983 Somatomedins in adolescence: a cross-sectional study of the effect of puberty on plasma insulin-like growth factor I and II levels. Journal of Clinical Endocrinology and Metabolism 57 268–271.

    • Search Google Scholar
    • Export Citation
  • Ma D & Jones G 2003 The association between bone mineral density, metacarpal morphometry, and upper limb fractures in children: a population-based case-control study. Journal of Clinical Endocrinology and Metabolism 88 1486–1491.

    • Search Google Scholar
    • Export Citation
  • Magarey AM, Boulton TJ, Chatterton BE, Schultz C, Nordin BE & Cockington RA 1999 Bone growth from 11 to 17 years: relationship to growth, gender and changes with pubertal status including timing of menarche. Acta Paediatrica 88 139–146.

    • Search Google Scholar
    • Export Citation
  • Magnusson P, Hager A & Larsson L 1995 Serum osteocalcin and bone and liver alkaline phosphatase isoforms in healthy children and adolescents. Pediatrics Research 38 955–961.

    • Search Google Scholar
    • Export Citation
  • Magnusson P, Larsson L, Magnusson M, Davie MW & Sharp CA 1999 Isoforms of bone alkaline phosphatase: characterization and origin in human trabecular and cortical bone. Journal of Bone and Mineral Research 14 1926–1933.

    • Search Google Scholar
    • Export Citation
  • Marowska J, Kobylinska M, Lukaszkiewicz J, Talajko A, Rymkiewicz-Kluczynska B & Lorenc RS 1996 Pyridinium crosslinks of collagen as a marker of bone resorption rates in children and adolescents: normal values and clinical application. Bone 19 669–677.

    • Search Google Scholar
    • Export Citation
  • Matkovic V 1996 Skeletal development and bone turnover revisited. Journal of Clinical Endocrinology and Metabolism 81 2013–2016.

  • Matkovic V, Ilich JZ, Skugor M, Badenhop NE, Goel P, Clairmont A, Klisovic D, Nahhas RW & Landoll JD 1997 Leptin is inversely related to age at menarche in human females. Journal of Clinical Endocrinology and Metabolism 82 3239–3245.

    • Search Google Scholar
    • Export Citation
  • van der Meulen MC, Carter DR & Beaupre GS 2001 Skeletal development: mechanical consequences of growth, aging, and disease. In Osteoporosis, edn 2nd, pp 471–488. Eds R Marcus, D Feldman & JL Kelsey. San Diego: Academic Press.

  • Meyer HE, Falch JA, O’Neill T, Tverdal A & Varlow J 1995 Height and body mass index in Oslo, Norway, compared with other regions of Europe: do they explain differences in the incidence of hip fracture? European Vertebral Osteoporosis Study Group. Bone 17 347–350.

    • Search Google Scholar
    • Export Citation
  • Mora S, Prinster C, Proverbio MC, Bellini A, de Poli SC, Weber G, Abbiati G & Chiumello G 1998 Urinary markers of bone turnover in healthy children and adolescents: age-related changes and effect of puberty. Calcified Tissue International 63 369–374.

    • Search Google Scholar
    • Export Citation
  • Mora S, Pitukcheewanont P, Kaufman FR, Nelson JC & Gilsanz V 1999 Biochemical markers of bone turnover and the volume and the density of bone in children at different stages of sexual development. Journal of Bone and Mineral Research 14 1664–1671.

    • Search Google Scholar
    • Export Citation
  • Moreira-Andres MN, Papapietro K, Canizo FJ, Rejas J, Larrodera L & Hawkins FG 1995 Correlations between bone mineral density, insulin-like growth factor I and auxological variables. European Journal of Endocrinology 132 573–579.

    • Search Google Scholar
    • Export Citation
  • Morishima A, Grumbach MM, Simpson ER, Fisher C & Qin K 1995 Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. Journal of Clinical Endocrinology and Metabolism 80 3689–3698.

    • Search Google Scholar
    • Export Citation
  • Nilsson LO, Boman A, Savendahl L, Grigelioniene G, Ohlsson C, Ritzen EM & Wroblewski J 1999 Demonstration of estrogen receptor-beta immunoreactivity in human growth plate cartilage. Journal of Clinical Endocrinology and Metabolism 84 370–373.

    • Search Google Scholar
    • Export Citation
  • Ninomiya JT, Tracy RP, Calore JD, Gendreau MA, Kelm RJ & Mann KG 1990 Heterogeneity of human bone. Journal of Bone and Mineral Research 5 933–938.

    • Search Google Scholar
    • Export Citation
  • Ohishi T, Takahashi M, Kawana K, Aoshima H, Hoshino H, Horiuchi K, Kushida K & Inoue T 1993 Age-related changes of urinary pyridinoline and deoxypyridinoline in Japanese subjects. Clinical and Investigative Medicine 16 319–325.

    • Search Google Scholar
    • Export Citation
  • Parfitt AM 1994 The two faces of growth: benefits and risks to bone integrity. Osteoporosis International 4 382–398.

  • Parfitt AM 2002 Misconceptions (1): epiphyseal fusion causes cessation of growth. Bone 30 337–339.

  • Parfitt AM, Travers R, Rauch F & Glorieux FH 2000 Structural and cellular changes during bone growth in healthy children. Bone 27 487–494.

    • Search Google Scholar
    • Export Citation
  • Pasco JA, Panahi S, Henry MJ, Seeman E, Nicholson GC & Kotowicz MA 1999 Femoral neck dimensions are unlikely to be associated with age at menarche. Osteoporosis International 9 557–559.

    • Search Google Scholar
    • Export Citation
  • Pfeilschifter J, Scheidt-Nave C, Leidig-Bruckner G, Woitge HW, Blum WF, Wuster C, Haack D & Ziegler R 1996 Relationship between circulating insulin-like growth factor components and sex hormones in a population-based sample of 50- to 80-year-old men and women. Journal of Clinical Endocrinology and Metabolism 81 2534–2540.

    • Search Google Scholar
    • Export Citation
  • Rauch F, Schnabel D, Seibel MJ, Remer T, Stabrey A, Michalk D & Schonau E 1995 Urinary excretion of galactosyl-hydroxylysine is a marker of growth in children. Journal of Clinical Endocrinology and Metabolism 80 1295–1300.

    • Search Google Scholar
    • Export Citation
  • Rauch F, Rauch R, Woitge HW, Seibel MJ & Schonau E 1996 Urinary immunoreactive deoxypyridinoline in children and adolescents: variations with age, sex and growth velocity. Scandinavian Journal of Clinical and Laboratory Investigation 56 715–719.

    • Search Google Scholar
    • Export Citation
  • Rauch F, Klein K, Allolio B & Schonau E 1999 Age at menarche and cortical bone geometry in premenopausal women. Bone 25 69–73.

  • Riggs BL, Khosla S & Melton LJ III 2002 Sex steroids and the construction and conservation of the adult skeleton. Endocrine Reviews 23 279–302.

    • Search Google Scholar
    • Export Citation
  • Riis BJ, Krabbe S, Christiansen C, Catherwood BD & Deftos LJ 1985 Bone turnover in male puberty: a longitudinal study. Calcified Tissue International 37 213–217.

    • Search Google Scholar
    • Export Citation
  • Rosenthal DI, Mayo-Smith W, Hayes CW, Khurana JS, Biller BM, Neer RM & Klibanski A 1989 Age and bone mass in premenopausal women. Journal of Bone and Mineral Research 4 533–538.

    • Search Google Scholar
    • Export Citation
  • Ross JL, Cassorla FG, Skerda MC, Valk IM, Loriaux DL & Cutler GB Jr 1983 A preliminary study of the effect of estrogen dose on growth in Turner’s syndrome. New England Journal of Medicine 309 1104–1106.

    • Search Google Scholar
    • Export Citation
  • Rotteveel J, Schoute E & Delemarre-Van de Waal HA 1997 Serum procollagen I carboxyterminal propeptide (PICP) levels through puberty: relation to height velocity and serum hormone levels. Acta Paediatrica 86 143–147.

    • Search Google Scholar
    • Export Citation
  • Roy DK, O’Neill TW, Finn JD, Lunt M, Silman AJ, Felsenberg D, Armbrecht G, Banzer D, Benevolenskaya LI, Bhalla A, Bruges AJ, Cannata JB, Cooper C, Dequeker J, Diaz MN, Eastell R, Yershova OB, Felsch B, Gowin W, Havelka S, Hoszowski K, Ismail AA, Jajic I, Janott I, Johnell O, Kanis JA, Kragl G, Lopez VA, Lorenc R, Lyritis G, Masaryk P, Matthis C, Miazgowski T, Gennari C, Pols HA, Poor G, Raspe HH, Reid DM, Reisinger W, Scheidt-Nave C, Stepan JJ, Todd CJ, Weber K, Woolf AD & Reeve J 2003 Determinants of incident vertebral fracture in men and women: results from the European Prospective Osteoporosis Study (EPOS). Osteoporosis International 14 19–26.

    • Search Google Scholar
    • Export Citation
  • Rozen GS, Rennert G, Dodiuk-Gad RP, Rennert HS, Ish-Shalom N, Diab G, Raz B & Ish-Shalom S 2003 Calcium supplementation provides an extended window of opportunity for bone mass accretion after menarche. American Journal of Clinical Nutrition 78 993–998.

    • Search Google Scholar
    • Export Citation
  • Sabatier JP, Guaydier-Souquieres G, Laroche D, Benmalek A, Fournier L, Guillon-Metz F, Delavenne J & Denis AY 1996 Bone mineral acquisition during adolescence and early adulthood: a study in 574 healthy females 10–24 years of age. Osteoporosis International 6 141–148.

    • Search Google Scholar
    • Export Citation
  • Schiele F, Henny J, Hitz J, Petitclerc C, Guenguen R & Siest G 1983 Total bone and liver alkaline phosphatases in plasma: biological variations and reference limits. Clinical Chemistry 29 634–641.

    • Search Google Scholar
    • Export Citation
  • Sen AT, Derman O & Kinik E 2000 The relationship between osteocalcin levels and sexual stages of puberty in male children. Turkish Journal of Pediatrics 42 281–285.

    • Search Google Scholar
    • Export Citation
  • Shaw NJ & Bishop NJ 1995 Mineral accretion in growing bones - a framework for the future? Archives of Diseases in Childhood 72 177–179.

  • Silbergeld A, Litwin A, Bruchis S, Varsano I & Laron Z 1986 Insulin-like growth factor I (IGF-I) in healthy children, adolescents and adults as determined by a radioimmunoassay specific for the synthetic 53–70 peptide region. Clinical Endocrinology 25 67–74.

    • Search Google Scholar
    • Export Citation
  • Silman AJ 2003 Risk factors for Colles’ fracture in men and women: results from the European Prospective Osteoporosis Study. Osteoporosis International 14 213–218.

    • Search Google Scholar
    • Export Citation
  • Slemenda CW, Reister TK, Hui SL, Miller JZ, Christian JC & Johnston CC Jr 1994 Influences on skeletal mineralization in children and adolescents: evidence for varying effects of sexual maturation and physical activity. Journal of Pediatrics 125 201–207.

    • Search Google Scholar
    • Export Citation
  • Slemenda CW, Peacock M, Hui S, Zhou L & Johnston CC 1997 Reduced rates of skeletal remodeling are associated with increased bone mineral density during the development of peak skeletal mass. Journal of Bone and Mineral Research 12 676–682.

    • Search Google Scholar
    • Export Citation
  • Smedsrod B, Melkko J, Risteli L & Risteli J 1990 Circulating C-terminal propeptide of type I procollagen is cleared mainly via the mannose receptor in liver endothelial cells. Biochemical Journal 271 345–350.

    • Search Google Scholar
    • Export Citation
  • Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB & Korach KS 1994 Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man [see comments] [published erratum appears in New England Journal of Medicine 1995 332 131]. New England Journal of Medicine 331 1056–1061.

    • Search Google Scholar
    • Export Citation
  • Sorva R, Anttila R, Siimes MA, Sorva A, Tahtela R & Turpeinen M 1997 Serum markers of collagen metabolism and serum osteocalcin in relation to pubertal development in 57 boys at 14 years of age. Pediatrics Research 42 528–532.

    • Search Google Scholar
    • Export Citation
  • Stanhope R, Preece MA, Grant DB & Brook CG 1988 New concepts of the growth spurt of puberty. Acta Paediatrica Scandinavica Supplement 347 30–37.

    • Search Google Scholar
    • Export Citation
  • Stear SJ, Prentice A, Jones SC & Cole TJ 2003 Effect of a calcium and exercise intervention on the bone mineral status of 16- to 18-year-old adolescent girls. American Journal of Clinical Nutrition 77 985–992.

    • Search Google Scholar
    • Export Citation
  • Szulc P, Seeman E & Delmas PD 2000 Biochemical measurements of bone turnover in children and adolescents. Osteoporosis International 11 281–294.

    • Search Google Scholar
    • Export Citation
  • Tanner JM 1975 Growth and endocrinology of the adolescence. In Endocrine and Genetic Diseases of Childhood and Adolescence, pp 14–64. Ed LI Gardner. Philadelphia: WB Saunders Company.

  • Theintz G, Buchs B, Rizzoli R, Slosman D, Clavien H, Sizonenko PC & Bonjour JP 1992 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. Journal of Clinical Endocrinology and Metabolism 75 1060–1065.

    • Search Google Scholar
    • Export Citation
  • Tobias JH & Compston JE 1999 Does estrogen stimulate osteoblast function in postmenopausal women? Bone 24 121–124.

  • Tobiume H, Kanzaki S, Hida S, Ono T, Moriwake T, Yamauchi S, Tanaka H & Seino Y 1997 Serum bone alkaline phosphatase isoenzyme levels in normal children and children with growth hormone (GH) deficiency: a potential marker for bone formation and response to GH therapy. Journal of Clinical Endocrinology and Metabolism 82 2056–2061.

    • Search Google Scholar
    • Export Citation
  • Tommasi M, Bacciottini L, Benucci A, Brocchi A, Passeri A, Saracini D, D’Agata A & Cappelli G 1996 Serum biochemical markers of bone turnover in healthy infants and children. International Journal of Biological Markers 11 159–164.

    • Search Google Scholar
    • Export Citation
  • Trivedi P, Risteli J, Risteli L, Hindmarsh PC, Brook CGD & Mowat AP 1991 Serum concentrations of the Type-I and Type-III procollagen propeptides as biochemical markers of growth velocity in healthy infants and children and in children with growth disorders. Pediatrics Research 30 276–280.

    • Search Google Scholar
    • Export Citation
  • Tuckermann JP, Pittois K, Partridge NC, Merregaert J & Angel P 2000 Collagenase-3 (MMP-13) and integral membrane protein 2a (Itm2a) are marker genes of chondrogenic/osteoblastic cells in bone formation: sequential temporal, and spatial expression of Itm2a, alkaline phosphatase, MMP-13, and osteocalcin in the mouse. Journal of Bone and Mineral Research 15 1257–1265.

    • Search Google Scholar
    • Export Citation
  • Varenna M, Binelli L, Zucchi F, Ghiringhelli D, Gallazzi M & Sinigaglia L 1999 Prevalence of osteoporosis by educational level in a cohort of postmenopausal women. Osteoporosis International 9 236–241.

    • Search Google Scholar
    • Export Citation
  • Veldhuis JD, Anderson SM, Patrie JT & Bowers CY 2004 Estradiol supplementation in postmenopausal women doubles rebound-like release of growth hormone (GH) triggered by sequential infusion and withdrawal of somatostatin: evidence that estrogen facilitates endogenous GH-releasing hormone drive. Journal of Clinical Endocrinology and Metabolism 89 121–127.

    • Search Google Scholar
    • Export Citation
  • Vihko R & Apter D 1984 Endocrine characteristics of adolescent menstrual cycles: impact of early menarche. Journal of Steroid Biochemistry 20 231–236.

    • Search Google Scholar
    • Export Citation
  • Weaver CM, Peacock M, Martin BR, McCabe GP, Zhao J, Smith DL & Wastney ME 1997 Quantification of biochemical markers of bone turnover by kinetic measures of bone formation and resorption in young healthy females. Journal of Bone and Mineral Research 12 1714–1720.

    • Search Google Scholar
    • Export Citation
  • Weise M, De-Levi S, Barnes KM, Gafni RI, Abad V & Baron J 2001 Effects of estrogen on growth plate senescence and epiphyseal fusion. PNAS 98 6871–6876.

    • Search Google Scholar
    • Export Citation