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Keywords:

  • menopause;
  • osteoporosis;
  • mechanical loading;
  • growth and development;
  • estrogens

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

The primary function of the skeleton is locomotion, and the primary function of estrogen is reproduction. When the skeleton is considered within this locomotive context, the onset of estrogen secretion at puberty leads to packing of mechanically excess mineral into female bones for reproductive needs. Accordingly, the unpacking of this reproductive safety deposit at menopause denotes the origin of type I osteoporosis.

Introduction: According to the prevailing unitary model of involutional osteoporosis, female postmenopausal bone loss can be described as having an initial accelerated, transient phase (type I), followed by a gradual continuous phase (type II). Estrogen withdrawal is generally accepted as the primary cause of the type I osteoporosis. Thus, the quest to uncover the origin of type I osteoporosis has focused on the estrogen withdrawal-related skeletal changes at and around the menopause. However, considering that the cyclical secretion of estrogen normally begins in early adolescence and continues over the entire fertile period, one could argue that focusing on perimenopause alone may be too narrow.

Materials and Methods: This is not a systematic review of the literature on the skeletal function of estrogen(s), but rather, an introduction of a novel structure- and locomotion-oriented perspective to this particular issue through pertinent experimental and clinical studies.

Results and Conclusions: When considering locomotion as the primary function of the skeleton and integrating the classic findings of the pubertal effects of estrogen on female bones and the more recent hypothesis-driven experimental and clinical studies on estrogen and mechanical loading on bone within this context, a novel evolution-based explanation for the role of estrogen in controlling female bone mass can be outlined: the onset of estrogen secretion at puberty induces packing of mechanically excess bone into female skeleton for needs of reproduction (pregnancy and lactation). Accordingly, the unpacking of this reproductive safety deposit of calcium at menopause denotes the accelerated phase of bone loss and thus the origin of type I osteoporosis.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

The role of estrogen has drawn the attention of skeletal researchers since Fuller Albright, a clinician working in the 1930s with a keen interest in research, introduced a classic concept on postmenopausal osteoporosis.(1,2) Albright(1,2) refused to put blame on coincidence that the majority of patients with frail bones were either naturally or “surgically” postmenopausal (older women who had gone through menopause, or alternatively, women in their 30s having undergone ovariectomy); Rather, he proposed that menopausal cessation of ovarian function and the consequent sharp reduction in circulating estrogen causes bone loss that ultimately results in the condition he termed postmenopausal osteoporosis in women who outlive the functioning of their ovaries.(3) Not only did Albright describe a new “disease,” but he also characterized the basic pathogenetic mechanisms of the condition, described strategies for treatment (supplementation of estrogen), and reported clinical outcomes after such treatment.

Since their introduction, the proposals of Albright have inspired numerous researchers to challenge, confirm, or refine this legacy.(4) Besides his proposal—the hypo-osteoblastic hypothesis with decreased bone formation—alternative explanations for the origin of the postmenopausal osteoporosis have included disturbance in osteoclasia with increased bone resorption,(5–7) negative calcium balance,(7–9) disturbance in calcium homeostatic control mechanisms,(10,11) increased skeletal sensitivity to parathyroid hormone,(12,13) deficiency of calcitonin(14,15) and calcitriol,(16) altered activities of growth factors and cytokines,(17–24) alterations in the local regulation of osteoclastogenesis,(25–29) changes in mechanical usage set-points,(30) failure in bone's adaptation to mechanical loading(31) and estrogen deficiency-induced inhibition of osteoclast apoptosis,(32) as well as derangement in the birth and death of osteoblasts and osteoclasts.(33)

Current understanding on the “macrodynamics” of bone loss in aging humans is probably best summarized in the model first presented by Riggs and Melton in 1986,(34) refined by Riggs et al. in 1998,(35) and extended by Riggs et al. in 2002.(36) The unitary model of involutional osteoporosis not only discriminates men from women but also divides the female postmenopausal bone loss into two separate phases: the accelerated, transient phase, (essentially the first decade after menopause accounting for 20–30% of cancellous bone loss and 5–10% of cortical bone loss [type I osteoporosis]), and the subsequent gradual, continuous bone loss (type II osteoporosis) that is apparently similar in both sexes.(34–36) This slow phase accounts for losses of about 20–30% in cancellous bone and about the same in cortical bone in both genders.(35) The model identifies estrogen deficiency as the primary cause of both the early accelerated phase and the late slow phase of bone loss in postmenopausal women and as a contributing cause of the slow phase of bone loss in aging men.(35) Although some of the details of this concept have been criticized, the prevailing view is that the root cause of the accelerated phase of bone loss is the withdrawal of estrogen.(37–40)

This being the case, it follows that pathogenetic mechanisms of type I postmenopausal osteoporosis (accelerated phase of bone loss) must be intimately related to a simple question: what is the primary function of estrogen in the female skeleton?

ESTROGEN-DRIVEN BONE PACKING IN PUBERTY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

The cyclical secretion of estrogen normally begins in early adolescence and continues throughout the entire fertile period (excluding periods of pregnancy) until the eventual cessation of female reproductive capability. It is noteworthy that previous hypotheses concerning pathogenetic mechanism(s) of type I postmenopausal bone loss have generally presumed that female skeletal mass (bone stock) existing before menopause under normal secretion of estrogen represents an appropriate baseline.(41,42) Thus, type I postmenopausal bone loss has been considered an inherent estrogen withdrawal-triggered failure in the delicate balance between the osteoblast and osteoclast activities that exists normally (e.g., before menopause). However, this view may overlook the potentially important role of estrogen in promoting the baseline level of mineral from which menopausal bone loss begins.

In this vein, we note that Albright actually proposed that estrogen triggers the build-up of calcium reserves in bone, from which calcium can be released into the bloodstream during pregnancy and lactation to serve the needs of the fetus and newborn. Some studies in pigeons strongly influenced Albrights's thinking and have been described as “the missing piece in his imaginary puzzle.”(3) These experiments(43–45) showed that not only the bones of ovulating female pigeons had much more endosteal bone than those of male pigeons but also that when estrogen was injected into male pigeons, the bone mass increased dramatically and reached the levels observed in healthy females. It is evident that these findings in pigeons may not necessarily apply directly to humans, because skeletal adaptation to the demands of reproduction is most developed in birds(46): before egg laying, the marrow cavities of certain bones are invaded by a complex network of cancellous bone, called medullary bone. This serves no mechanical role but functions as a mineral reservoir for eggshell calcification and quickly disappears after the final egg has been laid.(47)

Nevertheless, with regard to the estrogen-dependent reproductive phenomenon described in birds and its possible relevance to other species, Sherman and MacLeod showed in 1925 that, in rats, the female skeleton has significantly higher bone mass relative to the body and lean (muscle) mass than male skeleton.(48) These authors speculated, although did not directly couple the phenomenon to estrogen, that this extra packing of bone mineral into female skeleton was most likely an evolutionary safety measure against the anticipated bone loss caused by pregnancy and lactation. This finding of extra bone mineral relative to muscle mass was recently corroborated by more sophisticated means; Bowman and Miller(49) concluded that female rat has excess skeletal mass to compensate losses associated with the first reproductive cycle, and DeMoss and Wright(50) showed that while there was a difference in bone mass relative to body mass between sexes, the mineralization of bone material was identical. Rakover et al.(51) provided convincing evidence linking the extra mineralization of the female skeleton to puberty by showing that, compared with healthy controls, female rats with delayed onset of puberty (induced by repeated injections of gonadotrophin-releasing hormone antagonist) displayed significantly lower volumetric bone density but no difference in the bone cross-sectional area. And finally, in a very recent comprehensive analysis using both DXA and peripheral quantitative computed tomography (pQCT), Wang et al.(52) showed that from 1 to 6 months of age, the increase in total bone mineral content (BMC), cortical BMC, and cancellous BMC of the L4 vertebrae was faster in female than in male rats with similar muscle cross-sectional area. Most importantly, this gender difference resulted in significantly higher vertebral bone mass (both cancellous and cortical) relative to muscle mass in females than in males from 3 months.(52)

Such experimental observations were not linked to humans until 1998, when Schiessl et al.,(53) by re-analyzing the bone densitometric data of Zanchetta et al.,(54) showed that extra mineral is indeed deposited to female bones in puberty. In essence, it was shown that relative to the muscle activity-induced mechanical demands placed on bones—the primary regulator of bone mass, size, and shape(55,56)—girls have substantially heavier bones than boys at the corresponding age. Frost actually reiterated this phenomenon soon after its initial introduction in conjunction with his new “mediator model” for the estrogen-bone relationship and postmenopausal bone loss.(57)

HYPOTHESES OF OUR PARADIGM

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

Based on the evidence above, we outlined the following four hypotheses:

1. Relative to its primary function-locomotion, the bones of females become stronger (attain more mineral) than those of males in puberty

2. The puberty-associated extra packing of bone to female skeleton is estrogen-driven

3. The sex-related difference in skeletal mass/strength relative to locomotive needs is not a transient phenomenon limited to the most rapid period of skeletal growth (puberty), but a difference that persists over the fertile period

4. At menopause, there is a reversal of the above noted puberty-related packing of the skeleton—that is, an unpacking (net resorption) caused by estrogen withdrawal.

STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

Traditionally, nonmechanical functions of the skeleton (hematopoiesis and participation in mineral homeostasis) have been the main attraction of skeletal researchers. Accordingly, the effects of estrogen and other systemic (hormonal) factors on bone as a tissue have been characterized in detail.(36) However, today it is increasingly acknowledged that the primary function of bones is locomotion,(55,56,58) a change necessitating to broaden the scope from the tissue-level inspection to the evaluation of bones as structures.(58,59) To successfully carry out their locomotive function, each bone has a species-specific size, shape, and internal structure, the result of both phylogenetic and ontogenetic adaptation.(58,59) The precise spatial location of each bone element is probably quite secondary for the above noted subsidiary functions (hematopoiesis and mineral homeostasis), but it can be critical to bone strength, the bottom line.(60)

CORROBORATIVE EXPERIMENTAL EVIDENCE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

To test the above listed hypotheses within the structural and locomotive contexts, we first carried out three animal experiments.(61) In the first two experiments, we used 100 5- and 33-week-old female and male rats and observed a sex-specific difference in the sensitivity of bone to external loading: female rats exhibited a substantially lower responsiveness to external loading than male rats. Relative to body size and muscle weight (a surrogate of incident loading), the female bones were considerably stronger (and also had higher bone mass) than those of the males (Figs. 1A–1D). Subsequently we hypothesized that if the extra (mechanically excess) stock of mineral in female bones and the concomitant lower responsiveness to mechanical loading were truly attributable to estrogen, withdrawal of estrogen should not only reduce bone strength (through reduced bone mass and/or density), but also lead to an increased response to loading. Accordingly, in the third experiment, 60 littermates of 3-week-old female rats were subjected to ovariectomy or sham operation and then randomly assigned to treadmill training and control groups. At the end of a 16-week intervention, comprehensive densitometric and mechanical data confirmed that bone strength was reduced in the ovariectomized rats and that there was now better responsiveness to mechanical loading in these estrogen-depleted rats (Figs. 1E–1F). Thus, this experiment in female rats not only corroborated the above noted first three hypotheses on the skeletal effects of estrogen but also provided a plausible explanation for the accelerated phase of bone loss in women at menopause(35): once the female reproductive function ceases, the estrogen-driven packing of extra bone mineral to the female skeleton becomes useless, and accordingly, this mechanically excess mineral is shed from the bones.

thumbnail image

Figure FIG. 1.. The summary of the changes observed in our recent experimental series exploring the effects of sex and estrogen on the skeletal response to increased loading in rats. The effect of sex on the responsiveness of the incident loading related bone mineral content and fracture load in (A and B) growing and (C and D) mature rats (experiments 1 and 2). (E and F) In experiment 3, the effect of ovariectomy was assessed on the corresponding parameters. Bars represent the mean ± SEM. Control vs. exercise (within sex/estrogen status) differences in response to exercise are indicated as follows:*p < 0.05, **p < 0.01, ***p < 0.001. Between-sex/surgery (SHAM vs. OVX) difference in response (interaction) is as follows: #p < 0.05, ##p < 0.01, ###p < 0.001.

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Although the rat model is the most commonly used and validated model of experimental osteoporosis,(46,52,62–64) our conclusions need to be verified with human data. Thus, the ultimate question is what is the clinical evidence that there is estrogen-driven packing of extra mineral into female bones at puberty followed by a reverse unpacking phenomenon at menopause?

CORROBORATIVE HUMAN EVIDENCE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

To extend our hypotheses on humans, we first pooled the total BMC and body composition human data from studies of Zanchetta et al.(54) and Rico et al.,(65) the data covering the age range from childhood up to old age in both sexes (years 2–20(54) and years 15–83(65)). Figure 2 summarizes these clinical findings, clearly illustrating both the packing of excess mineral into the female skeleton at puberty and the subsequent unpacking of bone (the accelerated phase of bone loss) that starts at menopause. However, considering the methodological and analytical uncertainties in using DXA-derived total BMC and lean body mass as indices of bone(66) and muscle strength, as well as the potential importance (ramifications) of these findings, we also wanted to review other pertinent human studies.

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Figure FIG. 2.. The ratio of total body bone mineral content (TBBMC) to lean body mass (LBM) plotted against age. Data adapted from Zanchetta et al.(54) and Rico et al.(65)

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Schoenau et al.(67–70) were the first to provide evidence for a disproportionate increase in the strength of female bones relative to muscle strength (loading) at puberty by carrying out an extensive series of pQCT studies characterizing the interaction between bone and muscle in healthy children.(67–70) In an experiment with particular relevance to our paradigm, the authors aimed at confirming (or refuting) previous suggestions of Frost,(53,57) on mechanically excess pubertal packing of female bones.(67) Using pQCT, they determined the cross-sectional areas of cortical bone and muscle of radial midshafts (representing bone and muscle strength, respectively) on 318 healthy children (159 boys and girls) aged 6–22 years and 336 adults (parents).(67) Before puberty, the “bone strength-to-muscle strength” relation was identical in boys and girls, but at pubertal stage 3, the girls had a proportionally greater cortical cross-sectional area (bone strength). Accordingly, at the final pubertal stage or stage 5, girls were shown to have significantly stronger bones relative to the incident loading than boys.

Although estrogen has traditionally been regarded as a female sex hormone, estrogen is the major biologically active bone steroid in males also.(35,71–74) Studies on males with congenital estrogen deficiency caused by rare genetic defects—defect in estrogen receptor sensitivity(71) or estrogen synthesis(72–74)—have shown that in the absence of estrogen, the male skeleton displays continuous linear skeletal growth, open epiphyses, lack of a pubertal growth spurt, and most interestingly, reduced bone mass (reduced apparent bone density). These human genetic models or fundamental experiments of nature, as they have been described, have also provided one of the most convincing proofs for the causality of the pubertal bone-packing action of estrogen; patients with aromatase enzyme deficiency (thus lacking estrogens from birth and having very low bone density) were shown to respond to the administration of estrogen by a virtual complete reversal of the above noted skeletal disturbances, that is, the maturation of the skeletal growth plates, cessation of linear growth, and most importantly, increase in bone density.(73,74) In fact, this response (estrogen-induced deposition of mineral) has to be considered anabolic in nature(75): within 6 months of starting estrogen therapy, a patient with aromatization deficiency stopped growing with closure of all open epiphyses but simultaneously displayed a dramatic increase (∼20%) in apparent density of his bones,(74) indicating improved mineralization per unit area of bone substance.(75)

In summary, the above-noted studies in males with syndromes of estrogen deficiency or resistance, when combined with studies in males with aromatase excess resulting from an activating mutation of the aromatase gene with subsequently elevated estrogen concentrations,(76,77) corroborate our hypothesis regarding the timing and overall function of estrogen in skeletal development: they argue rather persuasively that the skeletal pubertal growth spurt is a function of estrogens rather than androgens—not only in female but also in the male skeleton,(75) and more importantly, that estrogen indeed induces the packing of mineral into the bones of girls as well as boys. These skeletal responses (mechanisms) observed in human “knockouts” have been corroborated experimentally in animal models in which the action of estrogen has been blocked either in the aromatization level(78,79) or receptor level.(80–82)

PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

What might be the evolutionary benefit for a link between this pubertal bone packing and female biology? Turner(46) suggested that, in mammals, increasing estrogen secretion during adolescence leads to increased cancellous bone volume, a stock of bone that can then be mobilized during pregnancy and lactation. Consistent with this notion, a number of recent experiments in rats provide evidence on the accumulation of excess mineral (mass) in developing female skeleton.(49,83,84)

Several recent longitudinal studies on pregnant and lactating women(85–87) provided an ideal opportunity to investigate the relationship between estrogen and bone. In these studies, it was shown that despite a high bone turnover state during pregnancy (supraphysiological levels of estrogen), the actual bone loss occurring in the mothers at this phase was modest. However, the high bone turnover state continued after delivery and resulted in a significant loss of bone mineral from the entire weight-bearing skeleton during the post partum amenorrhea (the first months after delivery). Bone mineral was regained after the resumption of menstruation (i.e., with the recovery of cyclic secretion of estrogen), although lactation continued. By coupling extensive laboratory measurements with the data from a longitudinal quantitative computed tomography scans, Ritchie et al.(87) were able to show that fetal calcium demand was met by increased maternal intestinal absorption, whereas the early breast-milk calcium was provided by maternal renal calcium conservation and loss of spinal trabecular bone, a loss that was recovered once menses returned.

Thus, it seems that in present day mothers, the skeletal changes observed during pregnancy (under supraphysiological secretion of estrogen) are relatively modest. It has been speculated that at least in the well-nourished women, the calcium required for fetal bone mineralization and accrual can be obtained by an increased efficiency of maternal calcium absorption in pregnancy, with no substantial need to mobilize maternal bone for this purpose. In line with this notion, the most recent evidence quite convincingly shows that there is no long-term detrimental effect of pregnancy or breast-feeding on the skeletal mass of the mothers.(88)

However, one should recall that the property of the female skeleton that we describe here (the estrogen-driven “extra” deposit of bone) is apparently evolutionary in nature, and thus 20th/21st century living is not comparable with the circumstances under which the mechanism initially evolved. For example, considering the current increased general knowledge on health issues and the higher standard of living—for example, the improved nutrition of pregnant/lactating women in comparison to women living, say 100,000 BC—some of the skeletal changes distinct at that time probably do not occur today, it is simply unnecessary.

Having said that, we illustrate such (above noted) bone changes actually occurring in the femoral neck of a mother with scarce supply and exceptionally high demand of calcium (extensive donor of breast milk) during postpartum amenorrhea (Fig. 3)(85): during pregnancy, she experienced only marginal bone loss (comparable with another mother with an adequate supply of calcium), but during the period of postpartum amenorrhea, the rate of bone loss was strikingly greater than in the other mother with a similar duration of postpartum amenorrhea. After resumption of menstruation, however, the recovery of bone mineral began in both mothers despite the continued lactation of the mother with the low calcium intake, providing another corroborative piece of evidence for our hypothesis on the reproductive function of estrogen on the female skeleton.

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Figure FIG. 3.. Changes observed in the femoral neck BMC in two mothers with discrete calcium supplies—a mother with adequate calcium supply and demand and a mother with scarce supply and exceptionally high demand because of excessive lactation (breast milk donor)—during pregnancy and postpartum amenorrhea. During pregnancy, the bone loss was comparable (approximately −4%) in both mothers, but a discernible difference was observed in the rate of bone loss during the period of postpartum amenorrhea: Virtually no further loss of bone was observed in the mother with normal supply, whereas a substantial loss was seen in the mother with a low calcium supply. After the resumption of menstruation, the recovery of bone mineral began in both mothers despite the continued lactation of the mother with the low calcium intake and high demand.

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To summarize, the maternity- and reproduction-related bone loss seems to be attributable mostly to the changes in estrogen status rather than resulting directly from the increased demand of calcium during pregnancy or lactation (skeletogenesis of the fetus and newborn, respectively). Overall, it seems that the proposals of Albright and his contemporaries regarding the function of estrogen as inducing a build-up of calcium “safety deposit” into female skeleton—a deposit from which calcium can be released into the bloodstream during pregnancy and lactation to serve the needs of the fetus and newborn—are also supported by the most recent scientific evidence.

SKELETAL FUNCTION OF ESTROGEN(S)

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

The tissue-level effects of estrogen and other systemic (hormonal) factors on bone have been characterized in detail and are summarized elsewhere.(36) However, bone is increasingly being understood as a structure,(58,59) and we discuss the effects of estrogen in that light here. The classic studies by Garn(89–91) suggested that estrogen primarily deposits the mineral on the endocortical surface of the female bones. The findings in men with congenital deficiencies in estrogen metabolism, in turn, suggest that estrogen brings about an actual “condensation” of bones.(74,75) Although the latter observations could naturally be deemed flawed as being derived from unnatural and/or abnormal circumstances (males, congenital deficiency), they could mutually be considered to disclose a mechanism common to both sexes, a mechanism of utmost importance concerning the skeletal function of estrogen. In fact, estrogen seems to result in the condensation (higher density) of the bones in healthy women, too, although quite understandably, the changes are not as dramatic as in males with congenital estrogen deficiency. In a recent pQCT-based study of 185 females and 177 males aged 6–23 years of age, the vBMD of the cortical compartment of the proximal radial diaphysis was similar in prepubertal girls and boys, but significantly higher (+3–4%) in females after pubertal stage 3, even after correction for the potential bias attributable to partial volume effect or difference in developmental stage.(69) Comparison of existing literature actually shows that the apparent volumetric bone mineral density (BMD) is indeed slightly higher in women than in men (+1–4%), particularly the vBMD of cortices.(92–95)

Schoenau et al.(67–70) also report data suggesting that female puberty leads to the acquisition of two types of calcium stores in cortical bone, the first created by apposition of bone on endocortical surfaces, and the second resulting from increased true mineral density in the cortical compartment. This finding of increased vBMD of the cortical bone is actually very interesting: the vBMD of the cortical bone, as an integrated measure of both cortical porosity and material density of cortical bone, is considered to reflect the metabolic activity of cortical bone (intracortical modeling). Accordingly, these findings of Schoenau et al.(69) suggest that intracortical remodeling is lower in postpubertal females than in males, which is in perfect agreement with the current view that estrogen primarily controls bone turnover.(96,97)

Keeping in mind that the estrogen-driven (mechanically excess) bone functions as a mineral reserve for the possible reproduction-related needs (fetal skeletogenesis, lactation), rather than the needs of locomotion, it is quite plausible that the requirements of reproduction also govern mineral deposition into the skeleton. Following this line of thinking, it is also most likely that the estrogen-driven additional mineral (bone) is deposited along the existing surfaces of both the cancellous and cortical bone compartments of the entire female skeleton. The most persuasive proof of the involvement of entire skeleton in this reproductive function is naturally provided by the fact that the estrogen-withdrawal related bone loss at menopause occurs from both compartments,(34–36) as well as the above noted studies on pregnant women showing that the bone loss is systematic and occurs from the entire skeleton.

Recent studies actually provide evidence that the cortical compartment would be predominantly involved in this task, at least concerning the appendicular skeleton: using pQCT, Uusi-Rasi et al. showed that users of hormone replacement therapy (HRT) have significantly higher volumetric BMD in the cortices of the tibial midshaft than the nonusers, the difference being about 1.5–3%. In the distal tibia containing both trabecular and cortical bone, in turn, the HRT-related effect was less distinct and also seemed to be mediated through change in the geometry of the cortical component but not through increased trabecular density.(98,99) As these findings were derived from cross-sectional studies, the causality between the apparent effects of estrogen on the postmenopausal bone is subject to uncertainties inherent to the study design. However, Cheng et al.,(100) in evaluating the effects of HRT and exercise in a 1-year longitudinal study on postmenopausal women using CT scanning, actually proved the causality by showing that in comparison with the placebo group, women on the HRT displayed a significant increase in the volumetric BMD of both the proximal femur (containing mostly trabecular bone) and tibial shaft (containing mostly cortical bone). By further analyzing the average bone mineral distribution across the bone cross-sections, the positive response of the cortical sites (tibial and femoral midshaft) to HRT was pinpointed predominantly to the endocortical region.(100)

In summary, considering that our hypothesis on the role of estrogen in regulating bone mass seems applicable not only on “hormone free, then hormone rich, then hormone deficient” states (packing at puberty and then subsequent unpacking at menopause) but also to a “hormone deficient-then rich again” situation (repacking of postmenopausal bones by HRT), we feel confident stating that estrogen indeed induces the packing of calcium/mineral into the skeleton.

BONE MASS AND FRACTURE “PARADOX”

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

The coupling of loading-induced mechanical strain to bone strength, the existence of a feedback mechanism establishing and maintaining bone strength through changes in bone mineral mass and architecture, was first suggested over a century ago(101) and has since received broad acceptance.(31,55,56,), 102 By linking the loading-driven homeostatic control system and estrogen withdrawal at menopause, an apparently paradoxical question arises as to why a mechanism that before menopause ensures that bones are sufficiently robust to withstand the loads of normal activity allows bone mass to decline after the menopause to the extent that fractures occur as a result of otherwise trivial loading events?(30,31) Accordingly, one could also claim that our suggestion that females have relatively higher bone mass than men is flawed, because women still experience more fractures (higher incidence) than men. However, what our data actually show is that, after puberty, the bones of women have, relative to the incident loading, more mineral than those of men. We are not claiming that in absolute terms women would have stronger bones than men. Rather, despite the pubertal packing of mechanically excess mineral into female bones, these bones are still smaller in size and have reduced cortical dimensions in comparison with men. Although the female bones are indeed sufficiently robust to withstand the loads of normal activity (day-to-day activities) even after menopause, a great majority of fractures do not occur as a result of otherwise trivial loading events but rather as a result of accidents (fall-induced trauma loading).(103,104) Hence, the bones of women are, because of their smaller size and cortical dimensions, more vulnerable to trauma loading, and consequently, women experience more fractures than men. When this is considered along with the fact that women fall twice as often as men,(105) it is actually quite plausible that they also experience more fractures than men.

ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

The above proposed estrogen-induced packing of mechanically excess mineral into bones in puberty also provides a credible mechanism for our previous studies concerning the timing of the most responsive period of female skeleton to mechanical loading: we previously pinpointed the most osteogenic period of growing female bones to the time immediately before and around the menarche.(106) We showed that racquet sports-induced benefit in the bone mass of the playing arm was about two times greater if women had started playing at or before menarche (the beginning of the cyclic secretion of estrogen) rather than after it.(106) We later corroborated this maturity-related change in the responsiveness of bones to loading with pQCT data.(92) Furthermore, we recently specifically tested a hypothesis that, in growing girls, the benefit of mechanical loading on bones is better before rather than after the menarche.(107) This study confirmed that, although a large proportion of bone mineral increase in the growing girls was attributable to growth itself, the exercise intervention resulted in a clear and large additional bone gain in exercising premenarcheal girls but not in exercising postmenarcheal girls. In other words, coherent with our hypothesis on the estrogen-induced bone packing of extra mineral in puberty and resulting lower responsiveness of female skeleton to mechanical loading, exercise seemed to be more beneficial for additional bone mineral acquisition before menarche rather than after it.(107)

We also note interesting observations in relation to mechanical loading and estrogen at the menopause (postmenopause). To our knowledge, there are three studies that have explored the effect of HRT and exercise in postmenopausal women using the appropriate 2 × 2 factorial study design.(108–110) In each of these studies, subjects with both HRT and exercise had the highest BMD compared with the other study groups after the completion of the intervention, a finding that has been misinterpreted as proof that estrogen enhances the skeletal responsiveness to loading. However, such a conclusion of better responsiveness would naturally have required a proper analysis, in which the actual within-group responses to exercise (change in BMD/BMC, controls versus exercise) were compared between the estrogen-deplete and -replete groups—this has not been done in any of these original studies. Therefore, we reanalyzed the data of these papers, and consistent with our hypothesis, a statistically significant BMD response was seen in the hip region of the estrogen-deplete women in all three studies, but no response in the estrogen-replete (HRT) women was found.

INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

Our hypothesis also provides a logical explanation to another unanswered question arising from the unitary model for the involutional osteoporosis; that is, why does the magnitude of accelerated bone loss caused by estrogen withdrawal vary considerably between individuals?(39) It is obvious that the estrogen-driven packing of extra bone mineral into female skeleton in puberty is dependent on the individual's genetic profile, as well as its reverse manifestation, the postmenopausal bone loss. The lack of an accelerated phase of bone loss in men is, in turn, most likely because of the simple fact that estrogen's reproduction-related action of packing excess mineral into bones in puberty does not occur in men rather than to lack of the menopause-equivalent period in middle-aged men, as believed today.(35,39) In this respect, in addition to the overall decline in the serum concentrations of many hormones, the declining muscle mass and physical activity leading to reduced skeletal loading are likely to play a significant role in the pathogenesis of the slow phase of bone loss seen in both women and men in later life (type II osteoporosis).(55,56)

ESTROGEN, EVOLUTION, AND BONE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

A famous population geneticist Theodosius Dobzhansky has stated that nothing in biology makes sense except in the light of evolution. Few would argue against the notion that the primary function of estrogen is to prepare the female body for the demands of reproduction. The extraskeletal effects of estrogen, such as the hypertrophy of the mammary glands and reproductive organs at puberty after estrogen secretion and the disappearance of these changes at menopause as a consequence of estrogen-withdrawal, are biological axioms. As our bones have been as much a part of biology as the rest of our body,(104) one could assume that the skeleton obeys similar mechanisms at menarche and menopause. Once mechanical loading (locomotion) is acknowledged as the major determinant of bone strength, and one measures the increased bone strength in pubertal girls (females) in comparison with boys (males), it becomes readily evident that there must be some other determinant of bone strength in the female population. There is indeed sexual dimorphism in the control of bone strength: the male skeleton is constantly under mechanical loading-induced control, whereas the female skeleton is apparently thrust into a higher (less responsive) level for the reproductive period. Our experiments and those of other show that the underlying mechanism for this additional bone strength is estrogen related, and we argue that the additional bone mass would provide a reservoir for reproduction—the female skeleton must be strong enough to produce new life and maintain it for a sufficient period of time. Being common to rats and humans, this estrogen-driven bone packing is apparently fundamental to all mammals—a mechanism that most likely dates back to 100 million years ago. Although our hypothesis regarding the effects of estrogen (estrogen-driven extra packing of bone mineral into female bones in puberty) partly contradicts Wolff's law(101) on how external loading controls bone mass, it underpins the overwhelming influence of estrogen and reproductive needs on the female skeleton. In women of childbearing age, estrogen simply overrides the loading-driven functional control of the skeleton, the primary regulator of bone size, shape, and architecture in men. In the end, it is only logical that the function of estrogen in the regulation of bone homeostasis is simple and ubiquitous as all fundamental biological processes generally tend to be as well as directly associated with estrogen's evolutionary function—reproduction.

FULLER ALBRIGHT WAS RIGHT, AFTER ALL!

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES

In summary, we highlight the primary assumption of Fuller Albright's that estrogen packs extra bone mineral into the female skeleton in puberty and extend this to propose a simple, evolution-based explanation for the pathogenetic mechanism of accelerated phase of postmenopausal bone loss. We underscore that estrogen deficiency-induced withdrawal of this stock of extra bone mineral is the origin of type I postmenopausal osteoporosis. Thus, the accelerated phase of bone loss at menopause simply results from withdrawal of this evolutional “safety deposit” of bone mineral when the female reproductive function ceases. In this context, we should recall that only relatively recently, in the 19th century, has the increased longevity introduced menopause and its consequences to the female population at large. Thus, rather than trying to provide a complex pathogenetic mechanisms for type I osteoporosis, such as an estrogen-withdrawal triggered failure in the control of bone mass, a simple evolution-based and biology-oriented explanation is more likely. As suggested by Fuller Albright in the 1940s, the answer to postmenopausal osteoporosis may well reside in puberty!

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. ESTROGEN-DRIVEN BONE PACKING IN PUBERTY
  5. HYPOTHESES OF OUR PARADIGM
  6. STRUCTURAL AND LOCOMOTIVE PERSPECTIVE—THE CORNERSTONE OF PARADIGM
  7. CORROBORATIVE EXPERIMENTAL EVIDENCE
  8. CORROBORATIVE HUMAN EVIDENCE
  9. PUBERTAL-PACKING, REPRODUCTION-RELATED, ESTROGEN-INDUCED SAFETY DEPOSIT OF CALCIUM?
  10. SKELETAL FUNCTION OF ESTROGEN(S)
  11. BONE MASS AND FRACTURE “PARADOX”
  12. ESTROGEN AND SKELETAL RESPONSIVENESS TO LOADING
  13. INTERINDIVIDUAL VARIATION IN THE MAGNITUDE OF ACCELERATED BONE LOSS DUE TO ESTROGEN WITHDRAWAL
  14. ESTROGEN, EVOLUTION, AND BONE
  15. FULLER ALBRIGHT WAS RIGHT, AFTER ALL!
  16. Acknowledgements
  17. REFERENCES
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