REVIEW Role of Oestrogen in the Regulation of Bone Turnover at The

223 REVIEW

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

Richard Eastell Academic Unit of Bone Metabolism, Division of Clinical Sciences (North), School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK (Requests for offprints should be addressed to R Eastell, Academic Unit of Bone Metabolism, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK; Email: [email protected])

Abstract The rise in oestrogen levels at menarche in girls is associ- and cancellous bone. The period of early puberty is ated with a large reduction in bone turnover markers. This associated with an increased risk of fracture, particularly reduction reﬂects the closure of the epiphyseal growth of the distal forearm, and this may be related to the high plates, the reduction in periosteal apposition and endosteal rate of bone turnover. A late menarche is a consistent risk resorption within cortical bone, and in bone remodelling factor for fracture and low bone mineral density in the within cortical and cancellous bone. Oestrogen promotes postmenopausal period; models that might explain this these changes, in part, by promoting apoptosis of chondro- association are considered. cytes in the growth plate and osteoclasts within cortical Journal of Endocrinology (2005) 185, 223–234

Introduction specific to bone, and their levels may be determined by changes in the rate of clearance from the circulation. The decrease in the levels of oestrogen at the time of the The alternative methods for studying bone turnover menopause results in an increase in the rate of bone include bone histomorphometry, calcium balance with remodelling and this plays a major role in the development kinetics, and radioisotope tracer methods. Bone histomor- of postmenopausal osteoporosis. These changes are phometry is based on a bone biopsy, usually taken from the dwarfed by the large increase in bone turnover that occurs iliac crest. This method has the advantage that it allows the at the menarche (Fig. 1). Indeed, the changes in bone study of changes to the two major cell types, osteoblasts turnover are matched by the changes in bone mineral – up and osteoclasts, and if tetracycline labels are administered, to 25% of total bone mineral accrual occurs over two years it allows the rate of bone remodelling to be measured. The at the time of peak height velocity (Bailey et al. 1999). drawbacks are that the biopsy is invasive, that the biopsy This review article will consider the role of oestrogen in site may not be representative of the entire skeleton, and the changes in bone turnover at the menarche, and the that only two biopsies may be taken in an individual’s consequence of these changes to an individual’s risk of lifetime. Calcium balance studies involve an in-patient stay fracture. 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 The study of bone turnover and that it gives an accurate estimate of balance, in contrast to the other two methods. However, the long hospital stay Methods means this is a very expensive approach and requires great Most of the information about the changes in bone attention to detail, and there are few places which cur- turnover at menarche and menopause come from the rently conduct such studies. Also, the mathematical models measurement of biochemical markers of bone turnover. to estimate calcium kinetics have never been standardised. These markers are measured in serum and urine and thus have the advantages that they can be measured repeatedly Bone turnover markers in an individual, they are relatively inexpensive, are non-invasive and reflect bone turnover in the whole The bone turnover markers are products of the osteoblasts skeleton. They have drawbacks in that they may not be or osteoclasts. The osteoblasts synthesise many proteins,

Journal of Endocrinology (2005) 185, 223–234 DOI: 10.1677/joe.1.06059 0022–0795/05/0185–223 2005 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org

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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.

and several of these are unique to the osteoblasts. The higher. The reason for the very high levels of bone immature osteoblasts secrete proteins such as the bone turnover markers in childhood is that they reflect not only isoform of alkaline phosphatase (bone ALP) which is the process of bone remodelling, but also that of growth. 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 Changes in bone turnover at the menarche its secretion from the osteoblasts. The mature osteoblasts secrete osteocalcin (OC), the marker that is most specific Description to the osteoblasts. The bone resorption markers are either degradation Bone turnover markers are high during childhood (relative products of type I collagen, or the enzyme tartrate resistant to adulthood) and there is a further increase during acid phosphatase (TRACP). Hydroxyproline makes up a puberty. With the onset of menarche, the markers all large part of the weight of collagen, but this amino acid is decline despite the high levels of insulin-like growth derived from other proteins, is absorbed from the diet, and factor-I (IGF-I). Many studies have investigated markers there is no immunoassay and so its use as a bone resorption of bone formation and resorption during childhood marker has fallen out of favour. The pyridinium crosslinks (Table 1). The changes in bone turnover with age are are formed between and within collagen molecules from similar to those reported by bone histomorphometry lysine and hydroxylysine residues once the collagen fibres (Parfitt et al. 2000). These studies consistently show that line up in a quarter stagger array. The crosslinks include bone metabolism rates are greater in children compared pyridinoline (PYD) and deoxypyridinoline (DPD); these with adults, with markers of bone formation and resorption may be excreted in the urine in the free form, or attached being several times higher compared with adults. The to the terminal residues of the collagen molecule, the so magnitude of this increase can vary greatly between called C- and N-terminal telopeptides (CTX and NTX). markers (Blumsohn et al. 1994). In the study by Blumsohn These bone turnover markers may be measured in et al. (1994) bone ALP increased tenfold but PICP only serum and urine (Table 1). Their measurement has been increased threefold in pubertal girls compared with the validated by the similar pattern with age in children adult reference range (Fig. 2). (Fig. 1), the relationship to height velocity (see below), Thus, the bone resorption marker, urinary NTX, is and by comparison with calcium kinetics, and compares 330 nmol bone collagen equivalents (BCE)/mmol creati- well, even in children (Weaver et al. 1997). nine (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). Changes in bone turnover across life A significant positive correlation between biochemical There has been a great deal of investigation into the markers of bone turnover and height velocity has been increase of 20 to 100% in bone turnover that occurs at described in several studies (Schiele et al. 1983, Kanzaki the menopause. However, the levels of bone turnover at et al. 1992, Hertel et al. 1993, Bollen & Eyre 1994, the menarche are up to ten times higher than in premeno- Kubo et al. 1995, Marowska et al. 1996, Rauch et al. 1996, pausal women, and the levels in the neonate are even

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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), Bone alkaline phosphatase (bone ALP) (Cadogan et al. 1998), (Mora et al. 1999), Osteocalcin (OC) (Magmusson et al. 1995), (Sorva et al. Procollagen type I C- and N-propeptides 1997), (Schiele et al. 1983), (van Hoof et al. (PICP and PINP) 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 resorption (Blumsohn et al. 1994), (Eastell et al. 1992), Hydroxyproline (Hyp) (Cadogan et al. 1998), (Mora et al. 1998, Galactosyl hydroxylysien (Gal-Hyl) 1999), (Beardsworth et al. 1990), (Ohishi Pyridinoline (PYD) et al. 1993), (Rauch et al. 1995, 1996), Deoxypyridinoline (DPD) (Fujimoto et al. 1995), (Libanati et al. 1999), N- and C-telopeptides of type I collagen (Slemenda et al. 1997), (Crofton et al. (NTX-I, CTX-I and CTX-MMP (ICTP)) 1997), (Shaw & Bishop 1995), (Tommasi Tartrate-resistant acid phosphatase et al. 1996), (Kikuchi et al. 1998), (Conti (TRACP) et al. 1998), (Bollen & Eyre 1994), (Bass et al. 1999), (Marowska et al. 1996)

Relative level (Tanner II & III vs. adult) 0246810

Osteocalcin Total ALP Bone i-ALP Bone w-ALP PICP Total DPD/Cr Free iDPD/Cr ICTP uGal-Hyl/Cr TRACP

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). www.endocrinology-journals.org Journal of Endocrinology (2005) 185, 223–234

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Figure 3 (A)and(B).

Sorva et al. 1997, Cadogan et al. 1998, Kikuchi et al. 1998, TIII) but the greatest mineral accrual occurs during mid to Bollen 2000). Longitudinal studies indicate that bone late puberty when markers are declining (Riis et al. 1985, turnover markers are maximal during early puberty (TI to Theintz et al. 1992, Del et al. 1994, Slemenda et al. 1994,

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Figure 3 (C). Figure 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 () 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. Adapted from Cadogan et al. (1998) with permission from the American Society for Bone and Mineral Research. Cadogan et al. 1998, Magarey et al. 1999). Cadogan increase in markers must be reflecting other processes. et al. (1998) reported that bone turnover markers were These include linear growth, which occurs at the epiphy- correlated to height velocity and not with bone gain seal growth plate, and modelling which includes changes (Fig. 3). Therefore Szulc et al. (2000) suggest that bone in shape and axis. The growth plate results in the produc- turnover markers are likely to reflect statural growth rather tion of new trabecular bone, and modelling results in the than bone mineral accrual. 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 What processes do the markers reflect? driven process, modulated by hormonal and dietary factors Bone remodelling is about three times higher in children (Beaupre et al. 1990, van der Meulen et al. 2001). These as compared with adults (Parfitt et al. 2000). Thus, the mechanical forces ensure that the section modulus of bone www.endocrinology-journals.org Journal of Endocrinology (2005) 185, 223–234

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closely follows body weight (and thus, muscle mass). The the arrest of growth and closure of the growth plate is exquisite sensitivity of bone growth to the daily stress now recognised by the report of cases of delayed closure in stimulus may explain why the benefits of physical activity men with oestrogen receptor deficiency (Smith et al. 1994) before menarche are so much greater than after menarche or aromatase deficiency (Morishima et al. 1995, Carani (Kannus et al. 1995). et al. 1997). Linear growth continues until age 16 in girls and 18 in The effects of oestrogen on modelling are to inhibit boys (Tanner 1975). Boys enter puberty two years later periosteal apposition and stimulate endosteal apposition. It than girls and the accelerated growth phase lasts one year is thus a key mediator of the sexual dimorphism of bone longer and hence boys are 10% taller than girls. Presum- and is the reason (along with the differences in linear ably, the greater increase in body weight and muscle mass growth, see above) why women have smaller bones relative in boys is providing a greater mechanical stimulus to bone to their size than men. The main effect of oestrogen on and thus the total body bone mineral is 25% higher in girls bone remodelling is to decrease it (see below). than in boys at the end of puberty (Riggs et al. 2002). Some studies report a strong negative correlation be- Some growth plates remain open until the age of 25, e.g. tween oestradiol and bone turnover markers in girls during those in the posterior spinous processes. Modelling is puberty (Blumsohn et al. 1994, Cadogan et al. 1998) maximal during puberty, continues until the third decade, although the finding is not universal (Rotteveel et al. and probably continues to a smaller extent throughout life. 1997). This observation would be consistent with the The continued opening of some growth plates and the known effects of oestradiol on the growth plate, the continued increase in size of bones by modelling, such as periosteum and remodelling. 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 How does oestrogen work? (Khosla et al. 1998). The effect of oestrogen on bone remodelling is to decrease activation frequency and subsequent decrease in the num- bers of osteoclasts and osteoblasts. The effects of oestrogen Why do the changes differ between markers? on the osteoclast are probably mainly indirect and medi- Not all markers behave the same. The increase in urinary ated by products secreted by the osteoblast. These products free crosslinks (e.g. immunoreactive (i)FDPD) increase include RANK-L (the ligand of the receptor activator of nuclear factor kappa B) and colony stimulating factor 1 less than telopeptides (conjugated crosslinks e.g. NTX). ff This may relate to renal handling of free and conjugated (CSF-1). They regulate the di erentiation of osteoclast crosslinks. It appears that up to half of free crosslinks are precursors to osteoclasts, and then modulate the activity generated within the renal tubule from conjugated cross- of the mature osteoclast and regulate its rate of apoptosis. links and that this process is rate limiting (Colwell & Oestrogen binds to receptors on the osteoblasts and Eastell 1996). Thus the changes in free DPD tend to be increases directly the production of osteoprotegerin (OPG) damped. PICP increases less than PINP. This may relate and decreases the production of CSF-1. Oestrogen de- to the induction of the mannose receptor by IGF-I; PINP creases the secretion of the pro-inflammatory cytokines is cleared by a different pathway, the scavenger receptor interleukin-1 and tumour necrosis factor-alpha by marrow (Smedsrod et al. 1990). Finally, the markers may differ in monocytes and this results in decreased production of their distribution – OC is rich in cortical bone (Ninomiya OPG and RANK-L by the osteoblasts, thereby decreasing et al. 1990, Magnusson et al. 1999) while bone ALP is the rate of production of osteoclasts, their activity and their present in the growth plate (Tuckermann et al. 2000). 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 & What is the role of oestrogen? Compston 1999). The effects on the growth plate have been studied in ovariectomised rabbits. Here oestrogen Growth, modelling and remodelling induces apoptosis of chondrocytes, resulting in arrest of Oestrogen has a biphasic effect on growth. By stimulating linear growth (Weise et al. 2001). Oestrogen receptors growth hormone (GH) production, it results in an increase (ER) (both and ) have been identified on chondrocytes in growth during puberty. This was well shown by Ross in the human growth plate cartilage and on osteoblasts et al. (1983) who treated girls with Turner’s syndrome on trabecular bone surfaces, which implies a direct action with ethinyl oestradiol. They found that low doses accel- of oestrogen on longitudinal bone growth and bone erated growth, whereas high doses slowed growth. Thus, formation (Kusec et al. 1998, Nilsson et al. 1999). at low doses, growth is accelerated but at high doses there The effect of oestrogen on bone cells is mediated is inhibition of growth and stimulation of fusion of the by both ER and ER. Using ER knockout mouse epiphyses (Parfitt 2002). The importance of oestrogen for experiments it is believed that the remodelling effects are

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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.

mainly mediated by ER, as are the growth plate effects, ing bio-available oestradiol (Pfeilschifter et al. 1996); the but the effects on the periosteum may be mediated by the consequence of this is to limit the actions of GH and IGF-I ER (Riggs et al. 2002). Interestingly, the effects of on bone. biomechanical forces appear to be mediated by the oestrogen receptor (Lanyon et al. 2004). What is the relevance to fracture risk?

How does oestrogen interact with GH and IGF-I? Fractures at puberty relate to bone mineral density There are a number of ways in which oestrogen and GH Fracture rate increases greatly at puberty in boys and girls. interact. (1) Oestrogen increases GH secretion by the It has been proposed that there is an asynchrony between pituitary at puberty, and this increased production has the peak height velocity and peak increase in bone mineral direct and indirect effects (by increasing IGF-I) on bone accrual, that latter following the former by about one year growth, modelling and remodelling. The effect of oestro- (Cadogan et al. 1998). This could be the case, but there is gen appears to be to augment growth hormone pulse a pitfall here – height is one dimensional, whereas bone amplitude (Veldhuis et al. 2004). (2) Growth hormone has mineral content is three-dimensional (it is distributed a major effect on bone, mainly through the local gener- within the volume of bone). ation of IGF-I. This stimulates the growth plate to increase The fracture rate around puberty (Fig. 4) is the highest the rate of growth. There are increases in IGF-I during during life (Bailey et al. 1989) – about one half of children childhood (Fig. 3), with peak levels during pubertal sustain a fracture, and half of these are forearm fractures, development in boys and girls (Luna et al. 1983, Silbergeld mainly occurring during early puberty (Jones et al. 2002b). et al. 1986, Cara et al. 1987, Johansen et al. 1988, Costin Also, these fractures have increased by between 30 and et al. 1989, Argente et al. 1993, Blumsohn et al. 1994, 60% in the past 30 years (Khosla et al. 2003). Moreira-Andres et al. 1995, Sabatier et al. 1996, Cadogan What is the mechanism for these fractures? It was et al. 1998, Libanati et al. 1999), and correlation with proposed that these resulted from high levels of physical height velocity (Silbergeld et al. 1986, Juul et al. 1994). activity, but this relationship is not proven (Blimkie et al. These studies also report that IGF-I correlates better with 1993). However, the risk of fracture relates to the level of Tanner stage than with chronological age. GH and IGF-I bone mineral density (BMD) (Jones et al. 2002a,Ma& increase the rate of bone remodelling. IGF-I stimulates Jones 2003) and to low BMD in mothers. Indeed, the low periosteal apposition. (3) Oestrogen antagonises the effects BMD might be explained by a thin cortical shell due to of GH and of IGF-I on the growth plate by stimulating endosteal resorption (Blimkie et al. 1993, Parfitt 1994, Ma fusion of the epiphysis (Ho et al. 1987, Stanhope et al. & Jones 2003). The timing of the increase in fractures may 1988, Matkovic 1996, Caufriez 1997). It opposes its effects relate to this increased cortical porosity in the distal radius, at the periosteum and on remodelling. (4) IGF-I lowers with calcium demand for bone growth being so high. the levels of sex-hormone binding globulin, thus increas- Presumably, the signal for increased cortical remodelling is www.endocrinology-journals.org Journal of Endocrinology (2005) 185, 223–234

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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).

parathyroid hormone (PTH), as the levels of this hormone Varenna et al. 1999), femoral neck (Gerdhem & Obrant are higher in early than in late puberty (Cadogan et al. 2004) and distal radius (Fox et al. 1993). Some of these 1998) (Fig. 3). An increase in PTH would indicate that effects could be mediated by changes in bone geometry, calcium supplementation might be beneficial; there have with a larger bone marrow cavity at the radius (Rauch been several clinical trials of calcium or milk supplemen- et al. 1999) but no changes to femoral neck dimensions tation at this age showing benefits on bone mass (Johnston (Pasco et al. 1999). et al. 1992, Lloyd et al. 1993, Lee et al. 1994, Chan et al. There are two hypotheses that might explain this associ- 1995, Bonjour et al. 1997, Cadogan et al. 1997, Dibba et al. ation (Fig. 5). The first of these relates to lifetime exposure 2000, Rozen et al. 2003, Stear et al. 2003). These studies to oestrogen. Thus, a woman with an early menarche showed consistent results despite the differences in the ages would have more years of exposure to oestrogen. How- of the subjects, forms of calcium used and in habitual ever, in the above studies age at menarche appears to have calcium intakes. As yet, there have been no clinical trials a stronger effect on fracture risk than age at menopause with fracture as the endpoint. (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 & Age at menarche is a major determinant of later fracture Obrant 2004) although some work does not support this A late menarche is a determinant of BMD in the older relationship (Ito et al. 1995, Varenna et al. 1999). woman and a strong risk factor for fracture risk. For The second hypothesis is that the body habitus that is example, the relative risk of hip fracture in women who associated with early menarche is associated with low risk had their menarche after the age of 17 was 2·1 (Fujiwara of fracture. Thus, girls who enter menarche earlier have et al. 1997), the relative risk of vertebral fracture in women higher body mass index (and thus serum leptin (Matkovic who had their menarche after the age of 16 was 1·8 (Roy et al. 1997)). They soon establish regular menses (Vihko & et al. 2003) and the relative risk of distal forearm fracture Apter 1984) (supporting hypothesis one) and they tend to in women who had their menarche after the age of 15 was be shorter and heavier (by 4 kg, on average) (Garn et al. 1·5 (Silman 2003). 1986). Slender stature is an important risk factor for hip Late menarche was associated with low BMD at the and spine fracture (Meyer et al. 1995, Roy et al. 2003), and lumbar spine (Rosenthal et al. 1989, Ito et al. 1995, tallness is a risk factor for hip fracture (Meyer et al. 1995).

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