Premenopausal Reproductive and Hormonal Characteristics and the Risk for Osteoporosis

C H A P T E R

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Premenopausal Reproductive and Hormonal Characteristics and the Risk for Osteoporosis John F. Randolph Jr.1, MaryFran R. Sowers†, 2 1Division

of Reproductive and Infertility, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA, 2Departments of Public Health, Internal Medicine, Obstetrics/Gynecology, Epidemiology­, and C ­ enter for Integrated Approaches to Complex Dis­eases, University of Michigan, Ann Arbor, MI, USA

INTRODUCTION Risk of osteoporosis and fracture in older women is, in large part, related to the woman's bone mineral density (BMD) [1]; however, the predisposition to osteoporosis and fracture may be established by the level of young adulthood peak bone mass. Stochastic models developed by Horsman and Burkinshaw [2] suggested that two-thirds of the risk for fracture can be predicted based on premenopausal BMD. Therefore, in premenopausal women, the primary goal is to maximize or maintain BMD. The World Health Organization (WHO) characterizes osteoporosis based on normative data from women aged 20–40 years. By the WHO [3] definition, osteoporosis exists when BMD is 2.5 standard deviations (SDs) below the mean values for women aged 20–40 years. Greater acquisition and longer maintenance of premenopausal bone mass can establish a bone mineral reserve that could ultimately reduce the risk for osteoporosis and fracture following menopause. Identifying those factors related to the accrual, maintenance, or diminution of bone is important given the difficulty in restoring lost bone. Reproductive activities and the hormones associated with reproduction may play a central role in BMD levels during pre- and perimenopause. In this chapter, those endogenous and exogenous events that are related directly or indirectly to the capacity to reproduce are considered for their importance to peak bone mass. In particular, this chapter includes updated information about bone loss in pregnancy, the importance of injectable and oral contraceptive pills (OCP) in peak bone mass, liberation of heavy metals

from the bone depot during pregnancy and lactation, and studies of luteal functioning and bone (see Chapter 44).

PREGNANCY Pregnancy and lactation are characterized by alterations in the maternal hormone environment, notably estrogen and prolactin concentrations. During the third trimester of pregnancy, estrogen levels rise as the placenta contributes large quantities of estriol [4]. In marked contrast, lactation represents a hypoestrogenic state with elevated prolactin concentrations [5]. These events are associated with a substantial calcium transfer from the mother for redistribution to the fetus or infant. The total accumulation of calcium in a full-term neonate during pregnancy is approximately 30 g [6]. If maternal bone was the sole source of calcium, the mother's skeleton would lose about 3% (30 g/1000 g) of its mineral per pregnancy. It has been unclear whether the size of the maternal bone depot is reduced during pregnancy. Typically, less than 20–30% of ingested dietary calcium is actually absorbed in an adult woman, and the remaining calcium is excreted in the feces. If absorption efficiency were doubled from 20% to 40% in women consuming moderate calcium intakes, the skeletal needs of the fetus could be met without extensively accessing the mineral stored in the maternal skeleton. Likewise, reducing maternal urinary calcium excretion could potentially also allow the demands of the mother and child to be met without an impact on the size of the maternal bone depot.

†Deceased.

Osteoporosis. http://dx.doi.org/10.1016/B978-0-12-415853-5.00030-3

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A number of metabolic adaptations take place early in pregnancy to address the mineralization demands of the fetus, including an increase in intestinal calcium absorptive capacity in response to an oral calcium load [7,8], a slowing of gastric motility, an increase in renal resorption, an increase in the extracellular fluid volume, an increase in urinary calcium excretion [9,10], and a modest decline in serum calcium concentrations in the second trimester [10,11], apparently in parallel with the decline in serum albumin [9,11–13]. This collective response would appear to preclude negative calcium balance [14–16] even in adolescent pregnant women [14] where the calcium needs to support fetal and maternal growth must be addressed.

Studies of Bone Mass and Pregnancy Until recently, studies of bone mass and pregnancy suggested either no measurable bone mass loss with pregnancy [17–20] or bone loss in specific compartments (trabecular rather than cortical) [21] or only at selected bone sites [22]. However, the growing availability and validation of bone ultrasound technology has changed our understanding of bone loss with pregnancy [23]. Now studies by Aguado et al. [24], Sowers et al. [25], Gambacciani et al. [26], and Tranquilli et al. [27] have all reported a modestly lower maternal bone mass with pregnancy, although an ultrasound-based study by Yamaga et al. [28] did not confirm this among Japanese women. These studies addressed many of the assessment issues associated with the use of dual-energy X-ray (DXA) densitometry during pregnancy. A net deficit in bone calcium balance, occurring during both pregnancy and early lactation, has been described with kinetics studies [29]. Early studies of DXA and pregnancy suffered from small sample sizes that lacked sufficient power to detect a 3–4% difference in bone mass change that might be expected during a pregnancy, but two more recent studies describe loss, then recovery [30,31]. Olausson et al. [30] evaluated 34 women prior to pregnancy and immediately postpartum and noted a 1% and 4% decrease in bone mineral content (BMC), areal bone mineral density (aBMD), and bone area-adjusted BMC at the wholebody, spine, and total hip. Moller [31] measured BMD and body composition in 153 women prepregnancy, in each trimester, and four times postpartum, noting similar loss during pregnancy and further loss with breastfeeding, but full recovery by 19 months postpartum. Substantial numbers of related unanswered questions remain, including whether women who are culturally or racially diverse have similar bone change responses with pregnancy, particularly in a calcium-deficient maternal environment. Studies had not addressed the issue of age (adolescent pregnancy or pregnancy at obstetric

maturity) and the potential for women in these groups to have different calcium needs and a different responsiveness of bone to the calcium demand of pregnancy on bone.

Studies of Bone and Pregnancy Using Biochemical Markers The most frequently characterized bone turnover markers measured in pregnancy include circulating osteocalcin and alkaline phosphatase (ALK) concentrations as indicators of bone formation. Until recently, markers of formation and resorption typically have not been reported simultaneously to more fully characterize the bone turnover experience. In a study of Italian women, it was reported that the resorption markers pyridoline and deoxypyridoline were lower in pregnant women as compared to controls [27]. Serum concentrations of osteocalcin tend to be comparable to control values in the first trimester, decline in the second trimester of the pregnancy, and then recover in the third trimester to levels observed in normal nonpregnant controls. This has been observed in studies with repeated measures [32,33] or static comparisons [7,34]. Rodin and colleagues [33] observed that concentrations were within normal range within 48 h of delivery. ­Notably, Sowers et al. [35] reported that the association of osteocalcin and insulin-like growth factor (IGF)-I in local bone regulation is different in women who are normotensive as compared to preeclamptic, so different turnover marker associations may be present depending on maternal health during pregnancy. Like osteocalcin, ALK has been evaluated as a marker of bone formation during pregnancy. Total serum ALK activity increases gradually in the first and second trimesters, with a rapid increase in the third trimester [11,13,33,36]. Rodin et al. [33] reported that both placental and bone-specific ALK isoenzyme patterns replicate the pattern seen in total ALK concentrations during pregnancy. Additionally, they documented that placental ALK declines to levels observed in the first trimester by 6 months postpartum; however, both total and bone-specific ALK are elevated at 6 weeks postpartum. In women who are lactating, activity remains elevated. More recently, Hellmeyer et al. followed bone resorption markers serum type I collagen C-telopeptides (CTX) and a crosslinked peptide of the carboxy-terminal telopeptide of type I collagen (ICPT) and formation markers bone alkaline phosphatase (BAP) and the N-terminal propeptides of type I collagen (PINP), and noted a significant increase in all markers over the course of pregnancy [37]. There has been only a preliminary examination of the role of the receptor activator of nuclear factor κB (RANK) ligand (RANKL) pathway in reproduction. These

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studies need to incorporate osteoprotegerin (OPG), an ­osteoblast-derived protein that binds to RANKL, a member of the RANKL-signaling pathway that regulates osteoclastogenesis and osteoclast activation [38]. One study indicates that there was no association of OPG with bone turnover and BMD during pregnancy, although the report was limited to data from 17 women [39].

Studies of Pregnancy and Calciotropic Hormones The numerous studies of calciotropic hormones (parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, and calcitonin) during pregnancy have been reviewed by Verhaeghe and Bouillon [40], Chesney et al. [41], Sowers [42], and Kovacs and Kronenberg [43]. PTH promotes increased calcium mobilization from bone in response to lower levels of circulating calcium concentrations. Initially, pregnancy was regarded as a state of “physiologic hyperparathyroidism,” as pregnancy was associated with an increase [34,36,44–46], in PTH concentrations. More recent studies, using more specific assays, challenged this concept and have reported either no significant elevation of PTH with gestation [10], or a decrease in PTH [46–50] relative to nonpregnant controls. The studies have generally not addressed dietary calcium intake, vitamin D status, or other factors that could, theoretically, influence PTH secretion. While the concept of “physiologic hyperparathyroidism” has been eclipsed, there is still the potential for functional hyperparathyroidism to exist in the absence of elevated PTH levels. Another agent, parathyroid hormone-related peptide (PTHrP), with sequence homology similar to PTH, has been described as being higher in pregnant women as compared to nonpregnant ­controls. In pregnancy, PTHrP appears to play multiple roles, including promoting maternal–fetal calcium transfer and milk production [51–54]. It is recognized that adequate vitamin D concentrations are necessary during pregnancy. Adequacy of vitamin D has been a source of concern, not so much for its association with bone loss, but because of the potential association with neonatal tetany. One review concludes that the evidence is contradictory (except for maternal infectious disease) and thus inconclusive that maternal vitamin D status influences maternal, fetal, and breastfed infant bone health, and maternal (preeclampsia, gestational diabetes, obstructed labor, and infectious disease), fetal (growth, gestational age, and developmental programming), and infant adverse outcomes [55]. During pregnancy, 1,25-dihydroxyvitamin D concentrations rise [11,13,32,47,56] and are believed to be responsible for the enhanced absorption of dietary ­calcium [46,47]. Those factors that regulate the hormone during pregnancy are uncertain, although PTH, growth

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hormone, prolactin, and estrogen have all been suggested as candidates [57]. It is not known whether the increased 1,25-dihydroxyvitamin D levels arise from the placenta. Alterations in the levels of 1,25-dihydroxyvitamin D are not associated with a similar pattern in the levels of 25-hydroxyvitamin D [57]. Investigators have observed that seasonal patterns in 25-hydroxyvitamin D levels in pregnant women are similar to those reported in nonpregnant women [13,45]. While it might be hypothesized that calcitonin concentrations should rise during pregnancy to protect the maternal skeleton from resorption, findings from the few studies of calcitonin concentrations during pregnancy have been inconsistent. For example, Stevenson et al. [58] and Whitehead et al. [49], in cross-sectional studies, reported an increase in calcitonin in pregnant versus nonpregnant women. Pitkin and colleagues [12] reported at least six different calcitonin patterns when multiple measures were made on study participants. Stevenson and associates [58] observed no difference ­ in calcitonin values between pregnant and lactating women. Synthesis of this information is difficult in that markedly different assays were used in these studies, limiting comparability. Additionally, there is now question as to how these assays relate to currently available and more specific calcitonin assays.

Bone Lead and Bone Resorption During Pregnancy There is concern that lead which accumulates in bone may be liberated during pregnancy and lactation, leading to adverse reproductive outcomes and impaired fetal development [59–63]. Reportedly, there were greater odds of having third trimester hypertension with higher circulating blood lead levels, although this was not observed with higher bone lead levels [64]. There is apparently no maternal–fetal barrier to lead [65]. In an adult, more than 90% of lead is deposited in bone [66], where it has a long half-life [67]. Thus, while legislative efforts to reduce lead emissions from combustion engines have led to remarkable reductions in mean blood lead levels [68], public health measures have not been universally implemented, and there is differential impact of lead exposures on population groups including children and the poor [69]. This, in combination with the long half-life of lead as well as other heavy metals such as cadmium in bone, has elevated the need for a better understanding of calcium dynamics and heavy metal exposures to new levels. A number of studies of bone and lead have taken place in Mexico City, where major exposures come from the use of leaded ceramics or result from breathing leaded gasoline emissions [70]. In studying ­Mexican women, Tellez-Rojo et al. [71] observed that plasma

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lead concentrations increased during pregnancy with greater bone turnover, as assessed by n-telopeptides, and higher bone lead levels, as assessed with K X-ray fluorescence. Among 367 breastfeeding women living in Mexico City, the highest breast milk lead levels were reported among those women who were exclusively breastfeeding and had high patellar bone levels [72], which is consistent with an earlier report among six lactating women where blood lead levels in breastfeeding women continued to rise, reaching maximum levels about 6–8 months following delivery [73]. Manton et al. also reported that levels dropped from one pregnancy to the next [73]. Based on these observations, both research groups have suggested that adequate intakes of calcium may be among the effective public health measures to minimize lead liberation from bone during breastfeeding. Manton suggested that a daily intake of 1000 mg during pregnancy may protect the skeleton from excessive lead resorption in late pregnancy [73]. There is some evidence that higher calcium intakes may afford some protection against lead exposures [74–76]. This apparent protection may be more relevant in those settings with high lead exposures such as residence adjoining a smelter [74]. Hernandez-Avila et al. [77] reported that among breastfeeding women of Mexico City with higher lead burden, a calcium supplement of 1200 mg of CaCO3 was associated with a ­modest reduction in circulating blood levels, subsequently reported to average 11% and to be most evident in the second trimester [78].

Summary and Implications Initial studies of bone change in pregnancy did not provide evidence of bone loss with pregnancy, although many of these studies had important design limitations. Studies of pregnant women using bone ultrasonography, DXA and bone turnover markers suggest that there is higher bone turnover and loss after 20 weeks of pregnancy. This occurs although fetal demand for mineralization of the skeleton is not particularly high (30 g), and there are adaptive mechanisms, including higher circulating levels of 1,25-dihydroxyvitamin D and increased intestinal absorption efficiency occurring simultaneously during pregnancy. This greater appreciation of bone turnover during pregnancy has motivated evaluation of the impact of bone turnover on the liberation of heavy metals, particularly lead, whose presence in the circulation may impact reproductive outcomes. Evidence continues to accrue that high lead levels in bone are accompanied by higher circulating lead levels, but these circulating levels might be modestly reduced through the use of calcium supplements.

AGE AT FIRST PREGNANCY Excess bone resorption with pregnancy may not be a characteristic of the mature woman who has achieved full maximal bone mass. However, evidence shows that pregnancy at an earlier age, when the skeleton of both fetus and mother are maturing simultaneously, may result in lower bone density and increased risk for perimenopausal bone loss. Sowers et al. [79] observed cross-sectionally that a first pregnancy during adolescence was associated with lower premenopausal radial BMD. A subsequent longitudinal study [80] showed that parous women whose first pregnancy was before 20 years of age had significantly lower age-adjusted baseline radial BMD, lower follow-up radial BMD, and greater 5-year radial BMD loss. The observation was confirmed by Fox et al. [81] in a cross-sectional study of about 1800 elderly women. The investigators speculated that the hormonal events of pregnancy during adolescence may jeopardize achieving the maximal peak in bone mineralization. Cho et al. noted similar findings in Korean women in a ­cross-sectional survey of postmenopausal women [82], and Schnatz et al. reported that both early pregnancy and no history of breastfeeding were associated with postmenopausal osteoporosis [83].

PARITY AND NULLIPARITY The relationship of parity to bone mass is complex and poorly defined. Theoretically, bone mass may decrease because of the calcium demand of pregnancy. In contrast, bone mass may increase with the greater circulating estrogen levels in the third trimester of pregnancy and because of the increased bone loading that occurs with the weight increases in pregnancy. With the uncertain impact of parity on bone mass, it is a logical extension that the impact of parity on fracture is also ill-defined.

Studies of Parity and Bone Mass A number of studies have reported an increase in bone mass with parity, as measured with different technologies at different bone sites with different parity classifications [81,84–87]. Other studies have found no association in studies of premenopausal [79,88,89] or postmenopausal women [90–93]. For example, in studies of Caucasian and Bantu women, Walker et al. [90] found no difference in metacarpal cortical area of women, ages 30–44 years, who had zero to one child as compared to those with more than six children. Likewise, Kritz-Silverstein et al. [94] reported no association with increasing number of

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pregnancies in women aged 60–89 years. Hreshchyshyn et al. [91] reported that BMD of the femoral neck declined with increasing number of live births, whereas there was no change in the lumbar spine. Henderson et al. [95] reported similar BMD levels in controls and women who had between 10 and 18 pregnancies and who breastfed almost continuously in the interval between pregnancies. Allali et al. noted decreased lumbar and total hip BMD with increased parity in a cross-sectional study of postmenopausal M ­ oroccan women, but no association with peripheral fracture rates [96]. Lenora et al., in a Sri Lankan population, and Turan, in Turkish women, found no cross-sectional association of multiparity or prolonged breastfeeding at any site in postmenopausal women [97,98]. Studies of parity and bone mass may have inconsistent findings because at least three factors may differ from one study population to another. These include differences in the ability to conceive, differences in the ­ability to maintain a viable fetus to term, and differences in the amount of weight gained during and subsequently retained following pregnancy. Successful conception and pregnancy require distinct hormonal environments. To conceive, the hormonal environment must be sufficiently competent to allow the preparation of the endometrial bed and development of the ovum. Bone mass measured in nulliparous women may not be the appropriate comparison to bone mass in parous women. ­Nulliparous women include those who lack reproductive competence, those who do not have the opportunity to conceive, and those who do not want to conceive. The lack of reproductive competence may be related to lower bone mass. Likewise, among those who do not want to conceive, the use of selected contraceptive preparations may be associated with lower bone mass, particularly if their use was begun during adolescence and prior to reaching peak bone mineralization. Studies of bone density and fractures in nulliparous women reinforce the concern that they are inappropriate controls for studies of parity and bone. In a longitudinal study of premenopausal women, Sowers et al. [80] found that nulliparity was highly predictive of reduced radial BMD, but not rate of change after controlling for age and body size. There was no relation between number of ­children and radial BMD when nulliparous women were not used as the referent group. Fox et al. [81] also identified that nulliparous women had significantly lower bone density of the distal radius among the postmenopausal women enrolled in the Baltimore Center of the Study of Osteoporotic Fractures. The lower radial BMD in nulliparous women suggests that their risk may be associated with an inability to conceive or maintain a pregnancy. Petersen et al. reported an increased risk of fracture with nulliparity compared to having at least one

child [99]. As such, careful interpretation of parity data is required if nulliparous women are an integral part of the reference population. Evaluation of parity in future studies should also include adjustment for confounders such as age of the mother and change in weight over time.

Studies of Parity and Fracture A longitudinal study [100] and a case–control study [101] provide evidence of a protective effect for parity in relation to hip fracture. In both studies, women with three or more children had an approximate 30–40% reduction in risk for fracture as compared to nulliparous women. While both studies addressed the contribution of other major potential confounders, the comparison groups, in both instances, were nulliparous women, groups whose biology may carry an intrinsic risk for low bone mass. If nulliparous women have lower BMD, they are likely to have a greater risk of fracture, and a parous group using them as a reference would appear to have an inappropriately reduced risk for fracture. A third study has identified a very modest protective effect of parity for hip fracture, but only among women who had not used OCPs [102]. Numerous studies have shown no association of parity with fracture. The studies, in widely diverse populations, include hospital-based case–control studies in Connecticut [103] and Toronto [104]; a populationbased case–control study in Seattle, Washington [105]; a case–control study of older women in southwest France [90]; a population-based case–control study in Australia [106]; and a cross-sectional survey of postmenopausal women in Morocco [96].

Summary and Implications It appears that if there is a protective effect of parity against fractures, mediated through greater bone mass, this effect is weak. A stronger case for a protective effect could be made for parity if the studies of both bone mass and fractures had used women with a single pregnancy as the comparison group and evaluated the likelihood of a “dose–response” with succeeding numbers of children. The status of these studies suggests that parity is neutral with respect to its impact on peak bone mass.

LACTATION Calcium Demand and Ovarian Suppression by Lactation At least two events that occur during lactation may have an impact on bone mass, including increased calcium demand and suppression of the

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hypothalamic–pituitary–ovarian (HPO) axis. There is substantial potential for significant calcium demand from the maternal skeleton. Mobilization of calcium from the maternal skeleton will be more highly variable than maternal skeletal mobilization in pregnancy, if it occurs, and the degree of calcium mobilization is dependent on the amount of breast milk produced and on the duration of the lactation period. An estimated cost to the maternal skeleton with 6 months of full lactation would be approximately 4–6% if no compensatory mechanism(s) existed for increasing calcium availability apart from mobilization of the skeletal depot. Calcium is transferred directly from serum to breast milk. It is estimated that approximately 600 mL/day of milk is produced at 3 months following parturition (168 mg calcium/day) and 1 L of milk is produced per day at 6 months following parturition (280 mg calcium/ day). The calcium concentration of milk is regulated and appears to be somewhat constant even in the face of variable maternal calcium intake. However, there is some debate as to the potential for lower calcium content of breast milk in women with very low calcium intakes, as evidenced when West African women were compared to British women [107]. It was initially assumed that there was an increased efficiency of calcium absorption in lactation, parallel to that observed in pregnancy. However, several studies, but not all [108], have reported that lactation is not associated with increased absorption efficiency [109,110]. In addition to the calcium demand with lactation, the hypothalamic–pituitary axis is suppressed in breastfeeding, as evidenced by the lack of luteinizing hormone (LH) release following administration of an estrogen challenge to lactating women [111]. Elevated prolactin concentrations associated with lactation inhibit pulsatile pituitary gonadotropic hormone secretion, suppress the positive feedback effects of estrogens, interfere with ovarian steroidogenesis, and induce ovarian refractoriness to gonadotropic stimulation [112]. Women with prolactin-secreting adenomas also illustrate the negative impact of nonlactational-elevated prolactin on bone demineralization [113,114].

Studies of Bone Mass and Lactation Studies of bone mass published between 1960 and 1990 were mixed with respect to the impact of lactation. Various studies suggested bone loss with lactation, no significant negative effect of lactation on subsequent bone mass or fractures, and even a rise in bone density with lactation. However, findings from longitudinal studies and clinical trials [115] have consistently shown significant early losses of BMD at the spine and hip in amounts of 5–7% of the total BMD [116–118]. The findings are also reported in animal studies [119].

Importantly, however, several of these studies have also documented that the bone mineral is largely restored in the 6- to 12-month period following weaning, as menses are reestablished [120]. Sowers et al. [121] reported that women who have lost bone mass during lactation appear to continue recovery during a subsequent pregnancy occurring within 18 months of the previous ­pregnancy. Further, lower BMD was not identified among women who continued to breastfeed during interpregnancy intervals that included 10–18 pregnancies and live births [95]. These changes in calcium homeostasis appear to be independent of lifestyle, including dietary calcium intake and exercise. Bone loss and recovery experiences have been reported to occur in Gambian women with low calcium intakes [122] as well as in groups of White women with greater calcium intakes [122]. Additionally, Little and Clapp [123] reported that regular, ­self-selected, recreational exercise has no impact on early postpartum lactation-induced BMD loss. However, more recently, Lovelady et al. demonstrated that a program of ­postpartum aerobic and resistance exercise reduces ­lumbar spine BMD and lean body mass loss during lactation [124]. Caird et al. [125] reported that the bone loss of l­ actation is somewhat minimized by the use of progestogen-only contraception. Nonetheless, biochemical marker concentrations measured in women using the progestogen closely resemble those observed in lactating women using barrier contraceptive methods. The mechanism(s) that mediates rapid bone turnover and mobilization of calcium from the maternal skeleton to breast milk is controversial. At least two possible mechanisms may increase skeletal turnover in lactation. The calciotropic hormones, PTH and 1­ ,25-dihydroxyvitamin D, stimulate bone resorption. Thus, it was believed that the transfer of calcium and phosphate to breast milk would stimulate PTH and 1,25-dihydroxyvitamin D-induced bone resorption. However, these actions have not been well substantiated in studies of lactation. Indeed, in the rat, it has been reported that the bone loss of lactation is independent of both PTH and vitamin D concentrations [126,127]. In humans, studies have frequently observed little difference in concentrations of these calciotropic hormones between lactating women and controls [128], but Carneiro et al. have shown an increase in both CTX of type I collagen and amino-terminal telopeptides of procollagen I during lactation, suggesting a coupled increase in osteoclast–osteoblast activity [129]. In mice, weaning induces an increase in serum calcium, decrease in PTH, and selective apoptosis of osteoclasts mediated through decreased levels of RANKL [130] leading to rapid recovery of bone mass. The changes in BMD with lactation appear to be determined by the combined effects of lower estradiol

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concentrations and higher PTHrP that may be linked with the higher prolactin concentrations [120]. Data suggested that the changes in calcium homeostasis during lactation are not related to PTH, ­1,25-dihydroxyvitamin D, or 25-hydroxyvitamin D concentrations or to the changes in the concentrations of these calciotropic hormones in the postpartum period [131]. Several lines of evidence suggest that PTHrP has a significant role in calcium metabolism in lactation. First, PTHrP was identified initially as the factor associated with the humoral hypercalcemia of malignancy that is expressed in multiple cancer types, but most notably with breast tumors [132–134]. Second, in animal studies, PTHrP has been shown to be synthesized in lactating mammary tissue [135,136]; in rats, a temporal relation exists between elevations in serum prolactin levels and the local expression of PTHrP mRNA levels [137]. High concentrations of PTHrP have been described in the milk of a variety of mammals [138,139]. In mice, the calciumsensing receptor is expressed on mammary epithelial cells and regulates PTHrP production and calcium transport in lactating mammary glands [140]. But, in mice with a conditional knockout of PTHrP in preosteoblasts and osteoblasts, there is no difference in lumbar spine BMC loss or recovery with lactation and subsequent weaning [141], suggesting that alternate mechanisms exist. Sowers et al. [120] found that elevated PTHrP concentrations were significantly associated with breastfeeding status, elevated prolactin levels, and lower estradiol levels, all conditions related functionally or ­endocrinologically to lactation. As shown with P values in Table 30.1, PTHrP was the consistent and significant predictor in all four of the femoral neck BMD change models and three of the four longitudinal models for

lumbar spine change, independent of the inclusion of serum prolactin or estradiol concentrations, time since resumption of menses, or breastfeeding practice. Furthermore, PTHrP values were associated negatively and significantly with BMD change in the spine and femoral neck over time. The primary role of PTHrP in calcium metabolism during lactation may be more prominent in the early months following parturition. Consistent with a linkage of greater prolactin and detectable PTHrP values is the report by Stiegler et al. [142] that detectable concentrations of PTHrP were observed in approximately 50% of men and women with prolactin-secreting adenomas and osteopenia. The transitory elevation in PTHrP concentrations as women initiate weaning might even contribute to the BMD recovery observed between 6 and 18 months following parturition. Using tissue culture systems of fetal rat calvariae, Canalis et al. [143] demonstrated that continuous treatment with PTHrP reduced labeled proline incorporation into bone collagen by 50%. However, transient exposure to PTHrP actually doubled the increase in proline incorporation, an effect that the investigators attributed to enhancement of the local production of IGF-I. Early in lactation, more constant PTHrP concentrations may be sustained by more frequent suckling. These sustained PTHrP concentrations, in turn, may minimize the amount of bone collagen formation and stimulate both bone resorption and formation. These actions would tend to assure a source of calcium and phosphate for incorporation into breast milk. Likewise, as lactation frequency subsides or as weaning is introduced, PTHrP secretion would become more episodic. Using as a paradigm the Canalis data as well as similar findings in studies conducted with PTH [144], one

TABLE 30.1  Longitudinal Regression Modelsa for Change in Spine and Femoral Neck Bone Mineral Density of Postpartum Women Breastfeeding practice Model

Time (months)

PTHrP (pmol/L)

Prolactin (ng/mL)

Fully

Partially

Estradiol (pg/mL)

Menses resume

I

(0.001)

(0.01)

(0.001)

—

—

(0.001)

—

II

(0.01)

(0.18)

—

(0.001)

(0.97)

(0.001)

—

III

(0.02)

(0.01)

(0.001)

—

—

—

(0.001)

IV

(0.06)

(0.03)

—

(0.001)

(0.15)

—

(0.01)

I

(0.06)

(0.02)

(0.01)

—

—

(0.18)

—

II

(0.04)

(0.01)

—

(0.01)

(0.01)

(0.26)

—

III

(0.08)

(0.03)

(0.03)

—

—

—

(0.18)

IV

(0.08)

(0.01)

—

(0.01)

(0.68)

—

(0.06)

SPINE

FEMORAL NECK

PTHrP: parathyroid hormone-related protein. a  P values.

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could speculate that bone mineral equilibrium would be restored and then measured as bone mass recovery. The multiple lines of evidence and the temporality provide a compelling argument for a biological role for PTHrP in calcium transfer during lactation. While there appears to be bone loss and bone mineral recovery with extended lactation, unanswered questions still remain. The mechanisms by which loss and recovery occur need further elucidation. Studies are needed in specific subgroups, including adolescents, women of obstetric maturity who are lactating, and women with extended and repeated lactation.

Studies of Lactation and Fracture The likelihood that lactation is associated with subsequent fracture risk appears to be influenced by the duration of the lactation [105] and by whether the comparison group is based on parous or nulliparous women [101,106]. For example, a case–control study investigating risk factors for fracture in postmenopausal women found no overall greater fracture risk in women who had breastfed versus women who had never breastfed [105]. However, stratified analysis suggested that breastfeeding for less than 1 year might increase the risk, whereas breastfeeding in excess of 1 year might decrease the risk. The case–control study by Kreiger et al. [103] suggested a protective effect for breastfeeding. The importance of comparison group definition is demonstrated in the data of Hoffman et al. [101] as well as Cumming and Klineberg [106]. Hoffman et al. [101] reported a protective effect of breastfeeding in relation to hip fracture (with confidence intervals that included the null value); however, that association could not be reproduced when the comparison was limited to parous women. In contrast, a negative association was reported by Cumming and Klineberg [106] that persisted when the comparison was restricted to parous women; however, confidence intervals for the measure of association included the null value. A study conducted in southern France showed no association of breastfeeding with subsequent fracture [145]. The most compelling evidence for a protective effect of lactation on subsequent fracture risk was reported by Bjǿrnerem et al. [146] who studied 4681 postmenopausal Norwegian women over 15 years for hip, wrist and proximal humerus fractures and noted no overall difference in fracture rates between parous and nulliparous women. However, women who breastfed had a 50% lower risk of a hip fracture and 27% lower risk of any fracture, and a marginally significant trend for a negative association of lactation duration and hip fracture risk after adjusting for body mass index (BMI) and relevant covariates.

Studies with Bone Turnover Markers Evidence supporting the observation of acute bone mineral loss and subsequent remineralization also comes from cross-sectional [116] and longitudinal [147], measurement of bone turnover markers and markers of calcium homeostasis [116,118]. Concentrations of osteocalcin [120,122] and bone-specific ALK reached their zenith in the early postpartum period and subsequently declined. Holmberg-Marttila et al. [148] found that both markers of formation and resorption were elevated at parturition and remained so in the early postpartum period, but extended the findings by identifying both higher parity and a longer history in the postpartum period compared to previously nulliparous women of the same age. The mechanism that might account for this accommodation has not been described.

Summary and Implications In summary, there appears to be little ultimate loss of mineral from the maternal skeleton with lactation of well-nourished women if, during or after lactation, menstrual cycling is reestablished. Current evidence indicates that extended lactation is associated with acute skeletal loss despite high dietary calcium intake. Variation in the calcium intake was not related to the amount of bone lost in either well-nourished or poorly nourished women. Likewise, calcium intake was not significantly associated with changes in bone turnover markers. The time to return of menses was consistently associated with time of bone mineral recovery. Presently, there is much to be learned about the mechanisms associated with the rapid loss during ­lactation as well as the rapid recovery of bone mineral that follows weaning. Investigations of PTHrP concentrations have been associated with the bone loss of lactation. Understanding these mechanisms could possibly be extended to other bone loss processes, including those associated with menopause, and potentially could serve as a model for facilitating bone mineral recovery.

OVARIAN ACTIVITY OR MENSTRUAL CYCLE CHARACTERISTICS AND BONE MASS The endocrinology of the ovarian cycle and the physiological manifestation in the menstrual cycle have not been well studied in relation to bone mass. This section addresses the onset of the menstrual cycle and explores the effects of subclinical and clinical disruption of the ovarian cycle.

V.  EPIDEMIOLOGY OF OSTEOPOROSIS

Ovarian Activity or Menstrual Cycle Characteristics and Bone Mass

Age at Menarche The initiation of menses and accompanying estrogen surge may stimulate bone growth by increasing osteoblastic activity [4]. However, the role of age at menarche relative to BMC could be defined more clearly if we understood whether age at menarche was related primarily to bone growth (and epiphyseal closure) or greater likelihood of mineralization as an adjunct to the increased likelihood of greater body size, or equally to both. Additionally, defining the initiation event for menarche, that is, hormone sensitivity or critical body fat mass, would also allow greater understanding about the long-term impact of the age at menarche on bone mass. Those with earlier age at menarche establish ovulatory cycles more quickly than girls with later age at menarche. Likewise, young women with early onset of menarche demonstrated greater concentrations of estradiol and follicle-stimulating hormone as compared to young women with later onset of menarche, while maintaining comparable body weights [149]. Two major hypotheses have emerged to explain the variation in age of menarche: one related to triggering of the pituitary–gonadal axis by maturation and the second associated with the achievement of a critical weight (body fat). Grumbach and colleagues [150] hypothesized that the onset of puberty is the result of decreasing hypothalamic sensitivity to gonadal steroids. The hypothesis postulates that the decreasing sensitivity results in increased output of the gonadal steroids (positive feedback), which ultimately brings about the m ­ orphologic and physiologic characteristics of sexual maturity. If this is the mechanism for menarche, it would imply that women with a delayed onset of menses might fail to establish higher concentrations of the gonadal steroids required for the feedback process. Such adolescents may have lower BMD if there is continued failure throughout early adulthood to establish a “normal” menstrual cycle pattern. The early version of the critical weight (body fat) hypothesis elaborated by Frisch and Revelle [151] proposed that menarche is achieved by attaining a critical body mass (as reflected by total weight). A secondary data analysis of three longitudinal growth studies suggested that the critical weight was 47.8 kg. The hypothesis was subsequently revised to suggest that the essential component of the body mass was in the fat compartment and that the critical fat level was 17% [152]. Frisch linked the critical fat hypothesis to hormone levels through the work of Nimrod and Ryan [153], who developed the concept of aromatization of androgens in body fat as sources of the estrogen estrone. The hypothesis has been highly criticized for its methodological and empirical limitations (reviewed by Scott and Johnston [154]). Whether weight acts as the precipitating or secondary

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event in the initiation of menarche, low weight (as a mechanical force) and low body fat mass (that becomes compromised as a secondary source of estrogens by the aromatization of androgens) have been suggested as risk factors for lower peak bone mass. A study of more than 2600 women in 512 pedigrees acknowledged the importance of environmental factors in age at menarche but suggested that the association was primarily attributable to shared genetic contributions rather than environmental factors [155]. This does not preclude the body fat hypothesis but may change the orientation to the genetic component of body fat accrual.

Studies of Bone Mineralization and Age at Menarche Numerous studies suggest that age at menarche is associated with bone growth and bone density. It has been observed that girls with an earlier onset of menarche are shorter, heavier, and have a shorter duration of bone growth than girls of usual age at menarche [156]. Conversely, girls with late age at menarche (14 years) are more likely to be taller, have lower body fat, and have lower bone density [155,157]. Later age at menarche is a risk factor for lower BMD [80,81,158] and for more rapid rate of premenopausal bone loss [76]. In the later study, there was no relation between age at menarche and radial BMD when nulliparous women were removed from analysis. Possibly, the hormonal environment that is associated with failure to conceive is the same environment associated with delayed puberty [80]. Age at menarche can be related to bone mineralization in at least two different ways. First, women with an earlier age at menarche are likely to have a longer time between menarche and menopause (gynecological age), a time during which estradiol resources are available to support and maintain bone mineralization. Second, events that precipitate earlier menarche, including weight gain, may be associated with characteristics that have been reported to produce greater bone density and, by imputation, greater peak bone density.

Menstruation and Number of Menstrual Cycles One reason that disparities may exist in assessing the role of reproductive factors is that the various events markedly alter the likelihood of exposure to specific levels of hormones. For example, with pregnancy and lactation, the effect of the elevated estrogen levels of pregnancy followed by the suppressed levels during lactation may generate a cumulative influence on bone density quite different from the influence of each event alone. One approach to accommodate these normal fluctuations in hormone levels is to examine the number of menstrual cycles. Fox et al. [81] showed a positive

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association between radial bone density in postmenopausal women with each successive year of continued menstruation. Georgiou et al. [159] reported that BMC in postmenopausal women was better explained by the total number of menstrual cycles than by the years since menopause or chronological age. Two reports indicate that women who always had irregular cycles had an increased risk of hip fractures compared to those who never had irregular cycles [160] as did women with infertility [161].

DYSFUNCTIONAL OVULATION Marginal Hormone Status Although the prevalence of frank estrogen deficiency has been estimated to be approximately 2% in collegeaged women, the prevalence in a general population, ages 20–40 years, is not well established. Furthermore, subclinical levels of estrogen insufficiency may be more common [162–164] and may influence bone density. Several studies have suggested that marginal hormone status is important in establishing variation in premenopausal BMD. Marginal hormone status associated with low premenopausal bone mass has been reported in three studies. Sowers et al. [163] described a nested case–control study in which significantly lower estradiol and testosterone concentrations and higher LH values were found in the low BMD group than in the control group. In a subsequent study, Sowers et al. [164] showed that daily urinary hormone excretion patterns for women with lower peak BMD differed from those of women with normal BMD. Healthy, menstruating women with low BMD from a large population-based study had significantly lower urinary sex steroid hormone concentrations during the luteal phase of menstrual cycles compared to hormone concentrations in premenopausal women with average BMD, even after considering the role of body size. Notably, LH peaks were lower and there was a muted progesterone response. These data suggest that subclinical decreases in circulating gonadal steroids may impair the attainment and/or maintenance of bone mass in otherwise reproductively normal women. Steinberg et al. [165] reported lower serum estradiol concentrations in perimenopausal women (mean age of 46 years) versus premenopausal women (mean age of 41 years). Free estrogen and free testosterone concentrations were positively correlated with bone density. These hormone characteristics were observed in populations without anorexia nervosa or intense chronic physical activity. In the Study of Women's Health Across the Nation (SWAN), Grewal et al. [166] reported that lower urine estrone conjugates and higher urine follicle-stimulating hormone

(FSH) were associated with lower spine and hip BMD in premenopausal and early perimenopausal women, but that short luteal phases or anovulatory cycles were not associated. These associations were consistent across four ethnic groups.

Pronounced Events of Ovarian Dysfunction Two syndromes that include amenorrhea, chronic endurance exercise and anorexia nervosa, have been characterized relative to bone density. It has been assumed that amenorrhea in both of these syndromes arises from reductions in total body fat rather than from intrinsic disruption of the neuroendocrine system. Two other clinical entities, prolactin-secreting tumors and polycystic ovarian disease, are less extensively studied relative to bone mass and are assumed to have primary involvement of the neuroendocrine system.

Chronic Endurance Exercise Premenopausal athletes are typically characterized by low body fat, less body mass, and greater BMD than nonathletes. However, it has long been appreciated that pre- and perimenopausal women who engage in chronic endurance exercise, if accompanied by menstrual dysfunction, may be catabolic rather than anabolic for bone [167–175]. The impact of long-distance training on female high school athletes is difficult to differentiate from osteopenia of adolescence as they achieve peak growth velocity, particularly in cross-sectional studies. For example, Kaga et al. [176] reported higher levels of osteocalcin and tartrate-resistant acid phosphatase and lower levels of BMD in high school athletes compared to adult athletes, although a number of investigators have identified a peak in height velocity and bone metabolite circulation around age 16 years [177,178]. Kaga et al. [176] concluded that the effect of long-distance training was different in adolescent versus adult athletes but did not account for the differences that might be observed during adolescence by including a control group of adolescents who did not engage in long-distance training. Reported menstrual cycle changes in women who exercise strenuously include delay in menarche [179], shortened luteal phase of the menstrual cycle [133], ­menstrual irregularities, oligomenorrhea, and amenorrhea [180,181]. Some investigators have suggested that the hypothalamic–pituitary–ovarian–adrenal axis is suppressed by rigorous physical activity; subsequently, bone mass is lower because of lower concentrations of estradiol [169,172,179,182] and progesterone [169] and higher concentrations of cortisol [183]. Another hypothesis is that lower BMD in female athletes is the ­consequence of repeated episodes of hyperprolactinemia [184], although increased basal prolactin values have not been identified

V.  EPIDEMIOLOGY OF OSTEOPOROSIS

Dysfunctional Ovulation

consistently in amenorrheic athletes [172,183,185]. Other studies have shown that progesterone, prolactin, and testosterone concentrations all increase with strenuous physical activity [186–188]. Frisch [189] argued that amenorrhea of exercise is due to a diminution of critical weight (fat mass). She further argued that there is a state associated with transitory weight recovery or moderate physical training that is accompanied by menstrual cycles that occur with shortened luteal phases or that are anovulatory. The critical weight hypothesis is not well supported in the literature, which indicates that both eumenorrheic and amenorrheic athletes may have similar amounts of body fat. For example, Myburgh et al. [190] found that amenorrheic athletes had lower BMD than controls, matched on age, body mass, and exercise quantity. This lower BMD was observed at the spine, proximal femur, and total body, but not at the midradial or tibial shafts. Linnell et al. [173] suggested that discrepancies observed in describing relationships between intense physical exercise and BMD may reflect the additive effect of low body fat and intrinsic ovarian dysfunction, indicating that these are not consistently simultaneous events. Prior et al. [162] concluded that decreases in spinal bone density among eumenorrheic women athletes correlated with asymptomatic disturbances of the ovulatory cycle and not with the degree of physical activity. Physical stress alone can influence menstrual cycling, regardless of body fat levels. Barrack et al. [191] noted that, in runners ages 13–18 years, menstrual irregularities, participation in five or more seasons of endurance running, BMI, and lean tissue mass were independent predictors of low BMD. While the catabolic effect of amenorrhea and strenuous endurance sports on bone mass in women is relatively consistently observed, demonstrating anabolic effects of fitness and moderate physical activity is more problematic. Potentially, fitness and moderate physical activity could be anabolic for bone by either hormonal mechanisms or increasing the mechanical loading on bone. A hormonal effect associated with physical fitness and body composition may be mediated through an increase in the secretion of growth hormone and thus somatomedin-C or IGF-I. This hormone apparently stimulates the intermittent secretion of PTH, collagen synthesis, and number of osteoblasts [192].

Amenorrhea of Anorexia Nervosa Osteoporosis is an established complication of anorexia nervosa [193–195]. Proposed mechanisms for osteopenia include estrogen deficiency, glucocorticoid excess [194], generalized malnutrition, and calcium intake deficiency, with the potential for more than one mechanism to be operating simultaneously. One hypothesis links decreased serotonergic signalling with

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activation of the sympathetic nervous system inducing decreases in bone mass through β2-adrenergic signaling in osteoblasts [196]. While some investigators have reported that the compulsive exercise frequently associated with anorexia nervosa was protective for bone loss [195], others have failed to observe this protective relation [194,197–199]. This discrepancy may be related to the degree and intensity of exercise practiced by study participants. In a Danish registry of persons diagnosed with anorexia and bulimia, fracture risk was almost two-fold greater (risk ratio (RR) 1.98, 95% confidence interval (CI) 1.60–2.44) in cases as compared with controls [200]. Because women with anorexia nervosa are frequently both underweight and amenorrheic, ascertaining the independent contributions of estrogen deficiency and decreased body mass to their osteopenia is difficult. However, in hyperprolactinemic amenorrhea, women with increased body weight are protected against osteopenia. This suggests the potential for independent contributions from both the underweight and hypoestrogenism [201]. Bachrach et al. [197] found body size, age at onset, and duration of anorexia nervosa, but not dietary calcium intake, physical activity level, or duration of amenorrhea to be correlated with BMD in adolescent girls. Dietary calcium supplementation has not promoted bone mineral maintenance; however, most studies acknowledge concerns about patient compliance with the therapy and short duration of therapy [194–197]. With rare exception [197], studies have failed to differentiate whether the subjects were women who had failed to acquire bone or women who had lost bone.

Hyperprolactinemia Gonadal suppression with prolactin-secreting tumors and other conditions associated with hyperprolactinemia may be an important contributor to low premenopausal bone mass and subsequent risk of osteoporosis in a ­limited number of women. It is estimated that hyperprolactinemia occurs in more than 25% of young adult women with amenorrhea. In a longitudinal study by Schlechte and associates [202], women with hyperprolactinemia had lower bone mass of the spine and radius at entry to the study. Over the 4.7-year follow-up, women with hyperprolactinemia did not lose bone mass, whereas healthy women had significant loss at the spine (but not radius). The investigators suggest that women with hyperprolactinemia may have retained bone mass in the face of decreased estradiol concentrations because of greater body mass (28 kg/m2 vs. 24 kg/m2) and higher testosterone concentrations. Restoration of gonadal function was not associated with normalization of the bone mineral [113,203].

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Klibanski and Greenspan [201] also reported that treatment improves bone density in women with hyperprolactinemia but does not return bone density to the level observed in controls. However, it has been observed that hyperprolactinemic women who were eumenorrheic had greater bone density than hyperprolactinemic women who were amenorrheic [203], suggesting the potential for a differential response according to the duration of reduced estrogen stimulation. Importantly, while hyperprolactinemia has been associated with decreased bone mass, weight gain, insulin resistance and endothelial dysfunction, it has not been associated with increased fracture rates [204].

Polycystic Ovarian Syndrome Polycystic ovarian syndrome (PCOS) is a heterogeneous group of conditions characterized by polyfollicular ovaries and an LH-dependent increase in androgen secretion. In addition to oligomenorrhea, this ­multifaceted syndrome may be accompanied by various degrees of virilization, obesity, hypertension, and diabetes. Di Carlo et al. [205] compared 188 women diagnosed with PCOS to a similar group of 142 patients with normal ovaries and reported that women with PCOS had significantly greater bone density of the lumbar spine (0.98 g/cm2 vs. 0.87 g/cm2). The same group also reported higher serum concentrations of LH, prolactin, and, as expected, testosterone. The investigators speculated that several factors may be associated with the greater BMD in the face of amenorrhea in this group. The PCOS group had a greater BMI (25.0 kg/m2 vs. 22.9 kg/m2) than women with normal ovaries and had higher androgen levels. More recently, using peripheral quantitative computed tomography (pQCT), Kassanos et al. found higher tibial volumetric cortical density in both obese and lean women with PCOS than control women, suggesting that mechanical load is insufficient to explain higher BMD [206].

Summary and Implications Among premenopausal women, there are variations in ovarian and gonadotropin hormones associated with variation in BMD. While the frank amenorrhea that may accompany chronic endurance physical activity, hyperprolactinemia, PCOS, and anorexia nervosa has long been recognized as being associated with lower BMD, the prevalence of these conditions is uncertain. Thus, it is difficult to ascertain the overall impact on peak bone mass and, by extension, osteoporosis, and fracture. New studies now indicate that lower concentrations of hormones jeopardize BMD even when amenorrhea is not present. This suggests that, as more is learned about the relationship between peak bone mass and osteoporosis

risk, premenopausal hormone administration may become a more prominent source of intervention.

ORAL CONTRACEPTIVE USE The impact of OCPs on BMC has been of great interest as investigators have tried to determine parallels between OCPs and menopausal hormone therapy on bone density. The lines between OCPs and estrogen therapy use have become increasingly blurred. OCPs are now approved for use in women over the age of 35 years, and estrogens are the common constituent frequently associated with both OCP products and menopausal hormone therapy. However, there are major differences in the drug formulation, including the presence or absence and types of progestins, the dosage of active ingredients, and the regimens for their use. The impact of OCP use on BMD remains unresolved, with studies reporting both no effect and a positive effect. In this review, both cross-sectional and longitudinal studies of OCP use and BMC were examined and, when possible, dichotomized according to menopausal status. This dichotomy is useful for the following r­ easons. First, formulations for OCPs used by women prior to 1980 (who are now more likely to be peri- and postmenopausal) generally had significantly higher estrogen doses than the preparations to which most premenopausal women have been exposed. Second, there may have been different selection factors operating as to which women elected to use OCPs in the 1960–1970s versus those currently using OCPs.

Studies of Oral Contraceptive Use and Bone Mass Findings from studies of OCPs and bone mass have been inconsistent, despite the substantial number of reports. The most consistent observation is that use of OCPs has not been associated with lower BMD. Whether OCP preparations are associated with greater BMD remains debatable. Numerous cross-sectional studies [207–211], have reported a positive association between bone density and OCP use in various populations of premenopausal women. Likewise, several studies have reported a positive association of OCP use across a wide age range, including postmenopausal women [212,213]. In contrast, other cross-sectional studies reported no association of OCPs with BMD in premenopausal women [202,214] and among women across a wide age range [91,215–217]. In one of the few longitudinal studies, Recker et al. [218] reported a positive correlation between total body bone mineral and OCP use; however, they observed no association between OCP use and BMD of the forearm

V.  EPIDEMIOLOGY OF OSTEOPOROSIS

Progestin-Injectable Contraceptives

or lumbar spine. In a longitudinal study with 5 years of observation, Sowers et al. [80] reported that among 22 pre- and perimenopausal women who had ever taken OCPs for more than 3 months, a longer duration of use was associated with less radial BMD loss, after adjusting for age. In a study of 19 women who were administered 20 μg of ethinyl estradiol and had bone measurements taken at the 3rd, 6th, and 12th cycle, the investigators reported a slight, but insignificant, rise in bone mass of the distal radius [219]. A major limitation of this study is the lack of a control group. In contrast, Gambacciani et al. [220] reported that 40- to 49-year-old women with oligomenorrhea using OCPs (20 μg of ethinyl estradiol) did not lose bone to the same degree as women with oligomenorrhea who did not use OCPs. It appears that an underlying assumption of BMD studies is that OCP preparations increase the circulating estrogen concentrations. However, many of the current preparations provide hormone doses just adequate to suppress ovulation and not sufficient to generate the variation in physiologic ranges found throughout the menstrual cycle in women not using OCPs. Most studies evaluating the potential effect of OCPs on BMD reflect estrogen dosages of 35 μg or greater. A study evaluating low-dose (20 μg) OCPs found BMD reduced in women using that pill [205]. There is good reason to believe that OCPs may help promote bone mineralization in women with very low circulating hormones, amenorrhea, or oligomenorrhea. There is less likelihood that BMD will be retained if the use of OCPs actually lowers circulating estrogen concentrations in any particular woman. Indeed, a study by Garnero and colleagues [221] indicated that there was no overall difference in BMD between users and nonusers; however, OCP use was associated with a moderate decrease in bone turnover.

Studies of Oral Contraceptives and Fractures The number of studies of OCPs and fractures is limited, in part because women who were of an age to use OCPs in the 1960s and 1970s are now achieving an age where fractures occur with sufficient frequency to make such a study efficient. A Swedish case–control study of OCP use and fractures suggested that the use of OCP in late reproductive life may reduce hip fracture risk in postmenopausal women (odds ratio (OR) 0.75, 95% CI 0.59–0.96) [222], which is in contrast with the experience in the 46,000 enrollees in the Royal College of General Practitioners Oral Contraception Study. The risk of subsequent fractures was significantly greater among OCP users than among nonusers [223]. In the Women's Health Initiative Observational Study, there was an adjusted relative hazard for fractures among past OCP users of 1.07 (95% CI 1.01–1.15), suggesting a very modest increased likelihood of having fracture in a cohort of 93,725 women

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aged 50–79 years old [224]. A Cochrane review found no randomized clinical trials of hormonal contraceptives with fractures as a clinical endpoint [225], not surprising given the usual ages of participants in such trials and the long lag before reaching significant fracture rates.

Summary and Implications While there have been a substantial number of studies that relate bone mass and OCP use, ambiguity remains. Findings about OCPs and bone mass may be difficult to synthesize for the following reasons. First, only some of the progestrogens are 19-nor-testosterone derivatives that have androgenic/anabolic properties. For example, Cundy et al. [226] reported that the degree of estrogen deficiency induced in women using depot medroxyprogesterone acetate (DMPA) for contraception may adversely affect bone density (see later). This is evidence for the importance of formulations of the particular OCP. Second, dose and duration of use may have a differential impact according to the chronological or gynecological age of the user. For example, the role of menopause may overshadow any impact of OCP use on BMD in postmenopausal women. The OCP effect may be different in adolescents still acquiring bone as compared to adult women who are more likely to be in a bone maintenance phase. Third, OCPs are also used in the regulation of dysfunctional menstrual cycles. As such, the universe of OCP users may be quite heterogeneous and include women with conditions that include potential hormonal abnormalities, for example, dysmenorrhea or irregular cycles, as well as women who use the hormones for contraception alone. Any future studies of OCP use should be undertaken in women in whom it can be determined if the hormonal preparation is being used for conception prevention or menstrual cycle regulation. Duration of use, as well as dose and type of the preparation, should also be addressed. In younger women, the issues of OCP use in bone acquisition versus bone maintenance should be addressed. In older women, the potential bone loss with age and menopausal status should be separated from the impact of duration of OCP use.

PROGESTIN-INJECTABLE CONTRACEPTIVES A progestin-only, injectable contraception, DMPA, given intramuscularly every 90 days, was approved for use in the US in 1992. Worldwide, the contraceptive DMPA is used in more than 90 countries by an estimated 3.5 million women. There is a compelling physiological mechanism by which DMPA could compromise BMD. Contraception is achieved primarily through disruption

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Mean percent spinal (L1-L3) BMD change

of the HPO axis. Because DMPA disrupts the HPO axis, it will suppress estrogen production, leading to a relative estrogen deficiency and a corresponding loss of BMD. If DMPA has an adverse effect on BMD, then a substantial cohort of young women may enter menopause with less bone mineral reserve and be at increased risk for the development of osteoporosis, fracture, and related morbidity following menopause. Many studies have addressed potential BMD levels among users. Collectively, they suggest that BMD values were approximately 3–7% lower than values in controls [226–229]. A 2-year study of 178 first-time nonadolescent users had mean hip and spine BMD losses of 5.7%, while 145 controls had less than 0.9% loss over the same period after a 24-month period (see Figs 30.1 and 30.2). Increasing BMI among DMPA users offered protection against DMPA-related BMD loss; however, calcium

intake, physical activity, and smoking did not influence BMD change in either group [230]. Two other studies of new DMPA users with a smaller number of users reported hip and spine BMD losses ranging from 1.5% to 3.3% [231,232]. Three longitudinal studies of predominantly long-term DMPA users reported minimal or no BMD loss [233–235], but these data did not indicate the status of BMD prior to DMPA initiation. Studies using biochemical markers (osteocalcin and n-telopeptides) indicated that both markers were higher, on average, than oral conceptive users, but were not markedly higher than nonusers [236]. Other studies suggest this BMD compromise may resolve following the discontinuance of DMPA use [228]. Clark et al. demonstrated that BMD loss slowed after 48 months of continuous DMPA use, and increased after discontinuation from 0.3% to 2.0% per year depending

1 0 −1 −2 −3

Control DMPA

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Average number of days from baseline

FIGURE 30.1  Mean percent changes in lumbar spine (L1–L3) BMD from baseline to 730 days for women using depot medroxyprogesterone acetate (DMPA) (---) and women using no hormonal method of contraception (—). Source: reprinted from [209], with permission from the American Society for Reproductive Medicine.

1 Mean percent hip BMD change

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FIGURE 30.2  Mean changes in total hip BMD from baseline to 730 days (2 years) for women using DMPA (---) and women using no hormonal method of contraception (—). Source: reprinted from [209], with permission from the American Society for Reproductive Medicine.

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Progestin-Injectable Contraceptives

on length of DMPA use and bone site [237]. Harel et al. reported that mean lumbar spine BMD returned to baseline within 60 weeks of the final DMPA injection, and increased 4.7% above baseline by 240 weeks [238]. Mean total hip and femoral neck BMD recovered to baseline more slowly, requiring 240 and 180 weeks, respectively, after the final DMPA administration. In 2004, the US Food and Drug Administration issued a black box warning on medroxyprogesterone-injectable contraceptive (Depo-Provera) about significant bone loss with use. The warning acknowledges that it is yet to be determined how much BMD recovery might occur with discontinuation (or the duration of time required for that recovery). DMPA potentially offers a model of the importance of ovarian hormones in the achievement and maintenance of peak BMD. Canterbury and Hatcher [239], found that mean serum estradiol concentrations in 207 women 3 months after DMPA injection were 52 pg/mL (SD not provided) compared to a mean estradiol concentration of 140 pg/mL reported for historical controls. Additionally, 25% of the women using DMPA (as compared to 15% of nonusers) had estradiol levels less than 15 pg/ mL, values similar to those of postmenopausal women. Furthermore, limited data document that DMPA disrupts the ovarian and menstrual cycles. During a normal menstrual cycle, the estradiol concentrations are at their lowest during the early follicular phase, rising to a peak at midcycle, followed by a decline and then presenting with a second peak during the midluteal phase [240]. Because DMPA inhibits the cyclical variation in estradiol concentrations, women using DMPA would experience a relative estrogen deficiency because of the absence of the increase in estradiol concentrations at the midcycle and during the luteal phase. Clark et al. [241] measured estradiol (E2) in serum collected weekly over an entire DMPA injection period of approximately 3 months and found average E2 concentrations at 20 pg/ mL (SD 13 pg/mL). Two other studies with three subjects each measured estradiol daily for 1 month prior to and up to 3 months after a single injection of DMPA of 150 mg [242,243]. Both studies observed the absence of the cyclical estradiol changes usually found during the normal menstrual cycle and estradiol concentrations that remained at levels consistent with the follicular phase of the menstrual cycle. Estimates of the frequency of amenorrhea vary by population and the duration of DMPA use. Large multinational studies report that between 35% and 66% of all women using DMPA will develop amenorrhea by 12 months, with 8–25% becoming amenorrheic after their initial injection. By the end of 5 years of use, approximately 70–80% of women will become amenorrheic [243–246].

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Because DMPA is widely prescribed to adolescents, there is a concern that suppression of the HPO axis by DMPA could lead to a compromise in the attainment of peak BMD among these young women. An observational study reported that there was evidence of bone mineral suppression in girls ages 12–18 years who were prescribed either DMPA or 20 μg ethinyl estradiol and 100 μg levonorgestrel compared to adolescents using no hormonal contraception [247]. A clinical trial in which the comparative arms were estradiol cypionate or placebo in adolescents who were receiving DMPA showed a positive BMD change from baseline (+4.7%) in adolescents randomized to the estradiol cypionate as compared to a negative loss from baseline (−5.1%) in those adolescents who were randomized to placebo [248]. A related issue is whether potential DMPA-related bone loss, particularly among adolescents, can be offset by a higher calcium intake and, if it can be offset, what setting will promote this behavior. Reasonable evidence shows that calcium intake influences bone acquisition in pre- and peripubescent girls [214,249,250]. However, some studies suggest that calcium intake influences only the timing, not the magnitude, of peak bone mineralization and that any effect may be best realized only in those persons with extremely low (500 mg/day) calcium intakes [251]. The research evaluating calcium intake and BMD in late adolescents or young adults is limited, and the few longitudinal studies specifically targeting women under age 40 are inconsistent. Recker and colleagues [218] found that calcium intake in 156 college women followed over 7 years was an independent predictor of bone gain over time. In contrast, dietary calcium intake, measured by both food frequency and 24-h dietary recall, did not predict change in radial BMD over 5 years in women aged 20–35 years. Similarly, no association was observed between calcium intake and change in BMD of the femoral neck and lumbar spine in 153 Finnish women aged 13–27 years who were followed for 15 years [252]. Weight gain is an acknowledged side effect of DMPA that could affect BMD. Physiologically, weight gain with DMPA could be due to an increase in muscle mass related to the androgenic effect of the progestin or to an increase in fat mass resulting from the inhibition of the appetite control center in the hypothalamus [253]. Weight gain could counteract the decline in BMD by providing an increase in the mechanical loading force on bone, stimulating osteoblasts and increasing bone formation [254]. An alternative counterforce might arise from the conversion of androgens to estrogen in the peripheral adipose tissue. As adiposity increases, there is a greater adrenal production of androgens that increases the availability of the precursor hormone, as well as an accelerated rate of conversion from androstenedione [255,256].

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Whether DMPA actually causes weight gain and the magnitude of that gain is controversial. Several international studies reported weight gains averaging 3 to 5 pounds at 12 months and 7 to 10 pounds at 24 months [257–260], but did not include a comparison to controls. Other studies provided no evidence of a DMPA-related weight gain [261,262]. However, one study reported an increase of 6.1 kg in 178 treated women compared to no increase in 145 controls over a 30-month observation period [263]. Further, substantial BMD loss occurred concurrently with this increase in weight that was associated with the fat mass compartment and not the lean compartment [263]. There are few reports of fracture risk with DMPA use, but Meier et al. noted an increase in fracture risk that rose as duration of use increased [264]. In a case–control analysis using the UK-based General Practice Research Database, 17,527 incident fracture cases and 70,130 control patients were identified with exposure to DMPA of 11% and 8%, respectively. Fracture risk was greatest in women using DMPA for longer than 2–3 years, was not different by age of user, and was not different from control women in users of combined OCPs. In summary, the widespread and international use of DMPA could result in a systemic reduction in BMD by disruption of the HPO axis. While some evidence suggests that this reduction is recoverable over time, a series of questions remain about its long-term impact. The primary question relates to whether its use among still-growing adolescents will reduce the potential for those adolescents to achieve their genetic potential for bone mass. A second issue arises when DMPA is used as the contraceptive method of choice in women who have been lactating. Whether the coupling of these two events that are associated with BMD loss could result in an additive bone loss is unknown.

OOPHORECTOMY Oophorectomy is commonly cited as an example of hypoestrogenism with an impact on measures of calcium metabolism [265], fracture [94], and BMC in both White [266–269], and Japanese women [270–272]. Richelson et al. [266] compared BMD of the radius, femoral neck, and lumbar spine in women in their fifth decade who had undergone oophorectomy 20 years earlier, with BMD measured at the same sites of women in their seventh decade who had undergone spontaneous menopause, also some 20 years earlier. BMD of the two groups of women were almost the same and suggested that estrogen is a factor as important as aging in determining the level of bone density. Indeed, Aitken et al. [267] reported that bone density, as measured by standard aluminum equivalents, was

lowest in women who had undergone oophorectomy at earlier ages.

Studies of the Effect of Oophorectomy on Bone Several studies have attempted to define the nature of the rate of bone loss following oophorectomy. Cross-­ sectional data of Stepan et al. [273] suggested a mean loss of 2.8% of the metacarpal cortical area and 8% of the lumbar spine (by dual photon densitometry) in the first year following oophorectomy. Using statistical modeling of secondary data of the cortical area, Reeve [274] projected that there was a doubling of bone resorption following oophorectomy. Genant et al. [275] estimated that annual bone mineral losses were approximately 8% in the vertebral spongiosum and about 2% in the peripheral cortex when evaluated by quantitative computed tomography. In contrast, Hreshchyshyn et al. [276] did not observe a more pronounced rate of change in women after oophorectomy as compared to naturally menopausal women. There was a modest increase in fracture risk (standardized morbidity ratio 1.4, 95% CI 1.0–2.0) among women in Rochester, Minnesota, who underwent bilateral oophorectomy between 1950 and 1979 [277]. Bone turnover markers reflect higher bone resorption relative to bone formation in the period following oophorectomy [270,273]. Investigators observed an increase in serum osteocalcin concentrations beginning 1–2 months following oophorectomy and increasing up to 1 year of follow-up. Bone-specific ALK also rose, although at a slower rate than osteocalcin levels [273]. Ohta et al. [270,271] proposed that the bone loss in women after oophorectomy encompasses more than the diminution of estradiol. Oophorectomy also includes a marked reduction of estrone and androstenedione concentrations to values that are significantly lower than those concentrations measured in menopausal women. These authors [270] indicated that postmenopausal women retain some estrone secretion from ovarian interstitial cells that may not be present in women with oophorectomy. A number of studies have reported that the calciotropic hormones, particularly PTH, do not undergo significant changes following oophorectomy [270,273,276], suggesting that the bone loss of oophorectomy is not dependent on the homeostatic regulation of serum calcium. Yet to be evaluated is the relationship to PTH, using a contemporary assay for intact PTH. While oophorectomy provides one model for the evaluation of ovarian hormone deprivation and BMD, that relationship may be confounded by those events that gave rise to the context for the oophorectomy. Oophorectomy with hysterectomy is performed for the treatment of malignancy, pelvic inflammatory disease, endometriosis, uterine fibroids, pelvic organ prolapse, and other

V.  EPIDEMIOLOGY OF OSTEOPOROSIS

Summary and Implications

conditions that may influence BMD independently of the surgical procedure and its hormonal sequelae. Estrogen replacement is a frequently proposed strategy following oophorectomy, although data describing the frequency of its prescription, compliance, and duration of use appear to be unavailable for the general population. Aitken et al. [267] estimated that women lost approximately 8% of metacarpal bone mass in the first 2 years following oophorectomy in comparison to no measurable loss in women treated with mestranol (10–20 μg/day). The same study also allotted a group of women to mestranol treatment who were 3 and 6 years postoophorectomy. While the women who were 3 years postoophorectomy maintained bone density, those women who were 6 years postsurgery continued to lose bone and manifested no responsiveness to the mestranol. The investigators interpreted this to mean that there is a limited window of time following oophorectomy when bone is most responsive to hormone replacement. A number of treatments for the bone loss associated with oophorectomy, apart from hormone replacement [278], have been evaluated. In a clinical trial of a synthetic flavonoid, Gambacciani et al. [279] demonstrated that women with oophorectomy/hysterectomy (n = 16) acting as controls had significant loss of radial bone mass and elevated hydroxyproline levels in comparison to women in the treated group (n = 16) 1 year following surgery. The prophylactic administration of salmon calcitonin in oophorectomized women apparently inhibited skeletal resorption as measured by radial BMC and the behavior of Gla protein (osteocalcin) and hydroxyproline concentrations [280].

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While the major concern of a negative impact of accelerated bone turnover during reproduction on subsequent risk of osteoporosis and fracture has largely been assuaged, there remains a concern about liberation of heavy metals from their bone depot. These concerns about adverse maternal and fetal outcomes arise when heavy metals, particularly lead sequestered in bone, are liberated during the more accelerated bone turnover of reproduction. Current investigations are centered around understanding the scope of the problem and methods to minimize the impact of the heavy metals. Studies of the reproductive environment and bone that have been reviewed support the concept that various hormone concentrations are important not only in their decline around menopause, but also in the establishment and maintenance of peak bone mass. The suppression of estradiol concentrations and the HPO axis in the use of DMPA as a contraceptive have a major effect on maintaining peak bone mass, to the degree that a black box warning by the US Food and Drug Administration has addressed the duration of DMPA use. There is still a need to understand the contributions of DMPA and lowdose contraceptives in relation to age and duration of use. The overt amenorrhea of prolactin-secreting tumor and chronic endurance exercise consistently validate the importance of an adequate estrogenic environment. This body of evidence suggests that a group of women could be identified who are at higher risk for compromise of their bone mass because of their hormone status. The evidence is sufficiently strong and the risk factors sufficiently potent to evaluate hormone and skeletal status in the period immediately prior to perimenopause.

References SUMMARY AND IMPLICATIONS A primary focus of studies of the reproductive environment has focused on the role of pregnancy and lactation as risk factors for subsequent lower BMD and increased risk of fracture. Collectively, studies of pregnancy and lactation have not shown that these events are obvious risk factors for sustained bone mass loss with a subsequent and adequate hormone environment that includes reestablishment of menses and the capacity to sustain continued reproduction. There is currently no evidence that multiple births interspersed with intensive lactation are deleterious to maintaining peak bone mass. Additionally, pregnancy and lactation provide models that can be examined to learn more of the biology associated with the maintenance of bone mass, particularly apart from calcium regulation by the calciotropic hormones. Lactation, in particular, offers the opportunity to understand the dynamics of bone loss as well as bone recovery.

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