Hypothalamic amenorrhea associated with low levels of caloric intake relative to high exercise energy expenditure leads to an energy deficit and subsequent hypoestrogenism that in turn is associated with clinical sequelae that include infertility, disordered eating, stress fractures, osteoporosis, and, as recently reported, a potential increase in the risk of premature cardiovascular disease [1–6]. Among exercising women, a condition describing the interrelated problems of disordered eating, menstrual irregularities, and bone loss, has been termed the female athlete triad . An understanding of the relation between these problems is crucial to understanding the mechanism of bone loss in exercising women, as the mechanical stimulus of weight-bearing exercise in women who are not energy deficient generally has a favorable impact on bone . The prevalence of triad disorders in female athletes ranges from 1% to 66% for menstrual disorders, 2% to 66% for disordered eating, and 6% and 48% for osteoporosis and osteopenia, respectively [8••].
Understanding the mechanism for bone loss in exercising women in the face of a chronic energy deficit is confounded by plausible independent effects of hypoestrogenism and food restriction on bone. It is well known that an energy deficit, here defined as energy intake that is inadequate for exercise energy expenditure, can be a key factor in the modulation of the reproductive axis [9–12] and a cause of decreased exposure of bone to circulating estrogen. However, caloric restriction alone, in the absence of changes in estrogen, has been shown to be an important factor in bone loss [13,14]. Evidence that these factors can both impact bone in women with hypothalamic amenorrhea includes several observations that oral contraceptive use in patients with anorexia or in women with exercise-associated amenorrhea is not associated with complete recovery of bone mineral density (BMD) [15,16]. Similarly, resumption of menses in formerly amenorrheic athletes does not result in complete recovery of BMD, and BMD has been shown to further decline in amenorrheic athletes if left untreated [2,17,18]. Thus, in addition to considering the degree of hypoestrogenism as a contributor of bone loss in women with severe exercise-associated menstrual disturbances, the impact of an energy deficit is also pursued as a potential cause of diminished BMD in this article.
Definitions, and Clinical and Endocrine Presentation of Severe Menstrual Disturbances in Exercising Women
A brief discussion and definition of severe menstrual disturbances, defined as primary or secondary amenorrhea, and oligomenorrhea, in exercising women is presented to correctly identify the specific populations discussed.
Secondary amenorrhea is associated with the most extreme deficiency in estrogen, and the most severe impact on skeletal health relative to other types of menstrual disturbances [5,7]. The definition of amenorrhea in the literature has varied but should be conservatively defined as no menses for a minimum of 3 months in a woman who has previously menstruated . This conservative definition of amenorrhea is used because the literature demonstrates that the risk of bone loss is greatest early after the onset of amenorrhea .
Amenorrhea in exercising women is hypothalamic in origin, presents with severely suppressed levels of circulating gonadotropins and ovarian steroids, and unaltered responsiveness of the pituitary gland and ovaries . Reports of the prevalence of amenorrhea in athletes range from 1% to 66% , and grossly exceed estimates of this condition in sedentary women (2%–5%) . The highest prevalence of athletic amenorrhea is found in sports that emphasize a low body weight such as figure skating, ballet, long-distance running, and gymnastics, but studies have documented menstrual abnormalities in a wide variety of sports .
Primary amenorrhea (delayed menarche)
Primary amenorrhea, or delayed menarche, is defined as the failure to achieve menarche by age 16 . Primary amenorrhea has also been repeatedly reported across a wide range of athletes, but particularly in cross-country running, ballet, and gymnastics . In most adolescents, the timing of menarche is very dependent on hereditary factors. Menarche, however, can also be influenced by other sociocultural factors, including the self-selective nature of participation in some sports, such as gymnastics and ballet, in which selection occurs for specific factors such as small frame or low body weight associated with a later age of maturation. In these adolescents, the later age of menarche is not necessarily associated with an aspect of the sport itself, but rather the type of athlete that excels in that sport. .
Oligomenorrhea is defined by irregular and inconsistent menstrual cycles lasting from 36 to 90 days in length , and represents a menstrual presentation that is difficult to study due to the nature of its inconsistent characteristics. As such, no definitive data exist on the prevalence of this menstrual abnormality in athletes, except to note that cycles of irregular length are often reported in female athletes . The presence of oligomenorrhea has frequently been grouped together with amenorrhea in a number of studies evaluating BMD [23–25]. The ovarian profile of an oligomenorrheic athlete displays erratic, unpredictable, and presumably low E2production as follicles struggle to achieve dominance. Oligomenorrheic cycles may be ovulatory or anovulatory, as the definitive event is the sloughing of the endometrial lining, which can occur in response to increasing E2 levels that are independent of ovulation.
Clinical Presentation and Prevalence of Decreased Bone Mineral Density in Exercising Women with Severe Menstrual Disturbances
Severe menstrual disturbances, defined as primary or secondary amenorrhea, and oligomenorrhea, have been unequivocally associated with decreased BMD in exercising women [1–3,23–25]. Despite the well-documented beneficial effect of weight-bearing exercise on bone, reduced BMD in amenorrheic athletes has been repeatedly reported, particularly in the lumbar spine, which is composed of primarily cancellous bone [1–3,23–27]. BMD can be decreased at multiple sites when amenorrheic athletes are compared with their menstruating counterparts. Although the most severe bone loss has been associated with amenorrhea, irregular menstrual cycles or oligomenorrhea has also been associated with low BMD in athletic women, and thus these less severe menstrual disturbances should not be dismissed clinically [23–27]. One study has reported that oligomenorrheic athletes have a lumbar spine BMD that is only 69% of that observed in an aged-matched cohort of menstruating women . It is important to note that not only is BMD associated with one's current menstrual status, but also one's history of menstrual disturbances, as shown by Drinkwater et al. . The latter point illustrates the cumulative impact of decreased estrogen exposure over many years.
Adolescence represents a critical period of rapid bone accretion toward the attainment of peak bone mass [28,29]. In young adolescents, primary amenorrhea and oligomenorrhea are especially concerning because long-term consequences are likely if their attainment of peak bone mass is compromised and presumably may increase the risk of future fractures from postmenopausal osteoporosis [5,27,30].
Decreased BMD in athletes is associated with an increased risk of stress fractures, nontraumatic fracture, fractures of the hip and spine, and an increased risk of associated injuries [5,31–33]. Specifically, studies of BMD in amenorrheic athletes show values equivalent to that observed in postmenopausal women, and likely accounts for the high rate of stress fractures observed in these young women [5,31–33]. Fracture risk, however, has not been clearly established in relation to BMD in this population. Other significant findings regarding BMD and amenorrhea are that the duration of amenorrhea is inversely related to BMD, and the risk of bone loss is greatest early after the onset of amenorrhea , underscoring the importance of effective and early intervention strategies. Especially in young adolescent athletes, clinicians are well advised to encourage nutritional intervention as soon as the problem is identified. As shown in Figure 1, the low BMD experienced by amenorrheic athletes is likely irreversible because resumption of menses offers very minimal improvements in BMD, permanently compromising the attainment of peak BMD in young athletes [2,17,18]. Even the administration of oral contraceptives and other hormonal replacement strategies fail to significantly improve BMD in amenorrheic athletes [15,34,35]. For example, Keen and Drinkwater  determined that after 6 to 10 years of normal menses or oral contraceptive therapy, lumbar spine BMD remained only 85% of that in athletes who had a history of regular menses. Thus, factors other than hypoestrogenism alone likely account for the diminished BMD in athletes with severe menstrual disturbances.
In athletes, bone loss more frequently meets the clinical criterion of osteopenia, not osteoporosis . Osteopenia is clinically defined as a T-score at any region of interest which is 1 to 2.5 standard deviations (-1.0 to -2.5) below the mean of that observed in young adults . Osteoporosis is clinically defined as a T-score in any region that is more than 2.5 standard deviations below the mean achieved in young adults. Where osteopenia is associated with a 100% increase in the risk of fracture in postmenopausal women osteoporosis represents an even greater risk of fractures . The prevalence of osteopenia in amenorrheic athletes is estimated to range from 1.4% to 50% [1,5,23–27]. The prevalence of osteoporosis is lower [23,38].
The International Society of Clinical Densitometry (ISCD) has recently recommended the use of a different set of clinical criteria that may be more appropriate in premenopausal women [39,40]. Specifically, they recommend the use of a Z-score, rather than a T-score, which represents comparison with aged-matched peers, in conjunction with secondary risk factors should be used [39,40]. These secondary risk factors include glucocorticoid therapy, hypogonadism, hyperparathyroidism, or an increased risk for fracture. The recommendation clearly states that BMD alone should not be used to define a diagnosis of osteoporosis in premenopausal women. Of significance, the ISCD has noted that all premenopausal women with low BMD should be evaluated for clinical and subclinical ovulatory disturbances.
Relationship of Bone Mineral Density to Hypoestrogenism and Energy Deficit
The following section addresses the interrelationships between energy deficit and the physiologic consequences of hypoestrogenism on the skeletal system.
Etiology of exercise-associated amenorrhea
During times of a chronic energy deficit, a shift in metabolic fuels occurs that repartitions energy away from the costly processes of reproduction and toward the essential processes of cellular, locomotive, and other life-sustaining metabolic functions . With respect to exercising women, eloquent short-term experiments by Loucks et al.  and Loucks and Thuma  manipulating both dietary intake and energy expenditure have demonstrated a relationship between energy status and luteinizing hormone (LH) pulsatility. Support for a causal relationship between energy status and menstrual cyclicity was provided by Williams et al. [11,12] who demonstrated that amenorrhea in exercising monkeys could be reversed by increasing food intake without any moderation in daily exercise training volume. Resumption of ovulation in the amenorrheic monkeys exhibited a dose-response relationship with energy availability, such that monkeys that ate more calories recovered ovulatory function more quickly than the monkeys that ate fewer calories. The additional observation in this study that changes in circulating total T3 was correlated with both the induction and reversal of amenorrhea lends support to the idea that the suppression of reproductive function is linked with adaptive mechanisms to reduce energy expenditure [11,12] in the face of inadequate caloric intake. Additional evidence for the relationship between energy availability and exercise-associated menstrual disturbances is found in cross-sectional studies of metabolic hormones and substrates that illustrate adaptive changes similar to that observed during episodes of chronic undernutrition [42–44]. These studies in amenorrheic athletes, combined with studies exposing metabolic endocrine signs of an energy deficit in exercising women with subtle menstrual disturbances such as luteal phase defects and anovulation  provide strong evidence that a hypometabolic state exists commensurate with exercise-associated menstrual disturbances. This hypometabolic state includes reductions in resting metabolic rate, total T3, leptin, insulin, glucose, IGF-1, and IGFBP-3 and elevations in IGFBP-1, ghrelin, growth hormone, and cortisol [42–44]. Changes in some of these metabolic hormones are documented to play a role in altered bone turnover that can contribute to bone loss, particularly a decrease in IGF-1 and leptin [46••].
Caloric restriction, weight loss, and skeletal health
Crash dieting, weight cycling, and disordered eating, including cognitive dietary restraint, are known to result in clinical sequelae, including menstrual cycle disturbances, decreased bone mass and fractures, and increased risk of osteoporosis [13,23,47–49]. Further, weight loss, calorie restriction, and restrained eating have all been associated with bone loss in humans [13,23,47–51]. In humans, a 10% decrease in body weight has been shown to result in a 1% to 2% loss in BMD [50,51]. This risk is exacerbated in low weight women. A significant percentage of premenopausal women, especially exercising women, utilize food restriction and exercise in their attempts to lose weight.
Beyond hypoestrogenism: bone loss in exercising women with an energy deficiency
Despite the known association between caloric restriction, weight loss, and skeletal health, it has generally been accepted that chronic hypoestrogenism is the major cause of bone loss in exercising women . During episodes of hypoestrogenism, osteoclasts are activated by circulating cytokines, thus promoting increased bone resorption . The physiologic evidence for the role of estrogen in bone mineralization has been reviewed elsewhere . Indeed, estrogen plays an important role in promoting bone mass in adolescents and young adults and in maintaining bone mass in adult women.
The effects of caloric restriction on BMD may be mediated by endocrine factors that may include an estrogen-dependent pathway, but may also include an estrogen-independent pathway that involves some of the metabolic-related hormones that are altered in exercising women with severe menstrual disturbances and that impact bone turnover. Because an energy deficit is a key factor in the modulation of the reproductive axis [9–12], our knowledge of the mechanism for bone loss with a chronic energy deficit is confounded by plausible independent roles of hypoestrogenism and caloric restriction on bone. Evidence that these factors can both impact bone includes several observations that oral contraceptive use in hypothalamic amenorrhea associated with anorexia, exercise or other functional hypothalamic causes is not associated with complete BMD recovery [15,16,18]. Similarly, recovery of menses in formerly amenorrheic athletes does not result in complete recovery of BMD and BMD has been shown to further decline in amenorrheic athletes if left untreated [3,17,18]. Other evidence in support of this concept is that eumenorrheic athletes are in some instances, reported to also display decreased BMD. Cobb et al.  observed osteopenia in 26% of regularly menstruating exercising women who met criteria for subclinical disordered eating, perhaps secondary to some degree of energy deficit-induced metabolic endocrine changes. Previous investigators concluding that hypoestrogenism contributes substantially to bone loss in premenopausal women most likely neglected to consider the potential for an additional and independent impact of calorie restriction on bone.
The effects of caloric restriction may independently affect bone through energy deficit-induced decreases in bone trophic factors, such as IGF-1 and leptin, or through micronutrient deficiencies of calcium, for example [14,46••,53–55]. Recent studies have utilized biochemical markers of bone turnover to assess the effects of an energy deficit on bone in exercising women with severe menstrual disturbances. Unlike the mechanism of bone loss in postmenopausal women, Zanker and Swaine  have shown that markers of bone formation (N-terminal pro-peptide of type 1 collagen [P1NP]) are suppressed in amenorrheic athletes, whereas markers of bone resorption (deoxypyridinoline [DPD]) are unchanged. Thus, unlike the postmenopausal, estrogen-deficient woman who exhibits increased bone resorption, the amenorrheic athlete does not. Figure 2 demonstrates the proposed mechanism of bone loss in amenorrheic athletes. Zanker and Swaine  also demonstrated that the lowest levels of the bone formation markers were observed in the amenorrheic athletes with the lowest total T3 and IGF-1. In the literature on anorexia, an energy-deficit model somewhat similar to amenorrheic athletes, but likely more severe, has demonstrated interesting observations that also support an energy-deficit–induced mechanism of bone loss [56,57]. Again unlike the amenorrheic athlete, patients with anorexia nervosa have both suppressed bone formation markers, but also increased bone resorption markers with a similar metabolic endocrine profile of amenorrheic athletes, but of greater magnitude of changes. During refeeding, recovering anorexic women exhibit a rapid increase in bone formation, followed by a more gradual decrease in bone resorption. Given the recent data published by Ihle and Loucks [58••], this is likely attributable to the estrogen deficiency requiring a longer intervention period of nutritional recovery for bone resorption to decrease, whereas early in the initial stages of refeeding, some of the metabolic endocrine disturbances are normalized.
Recently, Ihle and Loucks [58••] have eloquently demonstrated an intriguing relationship between varying levels of an energy deficit and markers of bone turnover in exercising women that significantly help to clarify the aforementioned relationships. A dose-response relationship between bone markers and reproductive and metabolic hormones was observed, such that at moderate volumes of energy restriction, markers of bone formation (osteocalcin, and C-terminal pro-peptide of type 1 collagen were suppressed, whereas severe volumes of energy restriction were required before bone resorption (N-terminal telopeptide) was increased. The increase in bone resorption was not observed, however, until a severe degree of energy restriction was imposed and was associated with a suppression of serum estrogen by 18% [58••]. The markers of bone formation, on the other hand, were decreased in a manner very similar to that observed for several metabolic hormones, including T3, insulin, and IGF-1, in conditions of a moderate degree of energy restriction [58••]. Figure 3 depicts these relationships. These data demonstrate a plausible estrogen-independent pathway whereby bone turnover, and specifically bone formation, is suppressed, and thus may contribute to decreased BMD in athletes experiencing a chronic energy deficiency. These findings may explain why reductions in BMD might be expected in eumenorrheic women with subtle and less severe menstrual disturbances secondary to an energy deficit, with or without weight loss, who also have slight metabolic hormone alterations indicative of a moderate energy deficit, but do not have severe reductions in estrogen.
Energy deficiency in female athletes and active women can give rise to hypoestrogenism and is associated with skeletal demineralization. Severe menstrual disturbances are a serious medical condition that signals concern for premature bone loss or the failure to achieve peak bone mass. The etiology of menstrual disturbances is causally linked to an energy deficit with a characteristic hypometabolic profile that includes alterations in bone trophic factors that may contribute to bone loss. Thus far, definitive experiments in exercising women with menstrual disturbances tease out the differential effects of hypoestrogenism and energy deficiency have not been conducted. However, studies revealing differences in the balance between bone formation and bone resorption in models of postmenopausal women who are hypoestrogenic but presumably not energy deficient and amenorrheic athletes who are both hypoestrogenic and energy deficient point to the plausible addition of energy deficiency to the mechanism of bone loss in these women. In addition, studies reporting otherwise unexplained compromised bone density in exercising women with normal menstrual cyclicity lend support to this idea. Expanding our understanding of the role of energy deficiency in bone loss associated with menstrual disturbances is important for designing optimal strategies for prevention and reversal of bone loss in exercising women, since a stronger emphasis on adequate nutrition, regardless of menstrual status, would be appropriate.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of major importance
1. Drinkwater BL, Nilson K, Chesnut CH, et al.
: Bone mineral content of amenorrheic and eumenorrheic athletes. N Engl J Med
2. Drinkwater BL, Nilson K, Ott S, et al.
: Bone mineral density after resumption of menses in amenorrheic athletes. JAMA
3. Drinkwater BL, Bruemner B, Chesnut CH: Menstrual history as a determinant of current bone density in young athletes. JAMA
4. O'Donnell E, Goodman J, Witt J, et al.
: Hypoestrogenism in amenorrheic athletes modulates cardiovascular function. Proc Am Coll Sports Med
5. Otis CL, Drinkwater BL, Johnson M, et al.
: ACSM position stand on the female athlete triad. Med Sci Sports Exerc
6. Zeni-Hoch A, Dempsey RL, Carrera GF, et al.
: Is there an association between athletic amenorrhea and endothelial cell dysfunction? Med Sci Sports Exerc
7. Marcus R: Role of exercise in preventing and treating osteoporosis. Rheum Did Clin North Am
8.•• De Souza MJ, Williams NI: Physiological aspects and clinical sequelae of energy deficiency and hypoestrogenism in exercising women. Human Repro Update
2004, epub 1 July.
Important paper presenting state of the information on the physiologic and clinical outcomes of energy deficiency and hypoestrogenism in exercising women.
9. Loucks AB, Verdun M, Heath EM: Low energy availability, not stress of exercise, alters LH pulsatility in exercising women. J Appl Physiol
10. Loucks AB, Thuma JR: Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women. J Clin Endocrinol Metab
11. Williams NI, Caston-Balderrama A, Helmreich DL, et al.
: Longitudinal changes in reproductive hormones and menstrual cyclicity in cynomolgus monkeys during strenuous exercise training, abrupt transition to exercise induced amenorrhea. Endocrinology
12. Williams NI, Helmreich DL, Parfitt DB, et al.
: Evidence for a casual role of low energy availability in the induction of menstrual cycle disturbances during strenuous exercise training. J Clin Endocrinol Metab
13. Shapses SA, Heymsfield C, Ricci TA: Voluntary weight reduction increases bone turnover and loss. Nutritional Aspects of Osteoporosis.
Edited by Burkhardt P, Haney R, Dawson-Hughes B. New York: Springer-Verlag; 1998:180–185.
14. Grinspoon SK, Baum HB, Kim V, et al.
: Decreased bone formation and increased mineral dissolution during acute fasting in young women. J Clin Endocrinol Metab
15. Hergenroeder AC, O'Brian Smith E, Shypailo R, et al.
: Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months. Am J Obstet Gynecol
16. Zipfel S, Seibel MJ, Lowe B, et al.
: Osteoporosis in eating disorders, a follow-up study of patients with anorexia and bulimia nervosa. J Clin Endocrinol Metab
17. Jonnavithula S, Warren MP, Fox RP, et al.
: Bone density is compromised in amenorrheic women despite return of menses: a 2-year study. Obstet Gynecol
18. Keen AD, Drinkwater BL: Irreversible bone loss in former amenorrheic athletes. Osteoporos Int
19. Beverly M, Biller K, Coughlin JF, et al.
: Osteoporosis in women with hypothalamic amenorrhea: a prospective study. Obstet Gynecol
20. Veldhuis JD, Evans WS, Demers LM, et al.
: Altered neuroendocrine regulation of gonadotropin secretion in women distance runners. J Clin Endocrinol Metab
21. Drew FL: The epidemiology of secondary amenorrhea. J Chronic Dis
22. Malina RM: Physical growth and biological maturation of young athletes. Exerc Sport Sci
23. Cobb KL, Bachrach LK, Greendale G, et al.
: Disordered eating, menstrual irregularity and bone mineral density in female athletes. Med Sci Sport Exerc
24. Gremion G, Rizzoli R, Slosman D: Oligo-amenorrheic long-distance runners may lose more bone in spine than in femur. Med Sci Sports Exerc
25. Tomten SE, Falch JA, Birkeland KI, et al.
: Bone mineral density and menstrual irregularities. A comparative study on cortical and trabecular bone structures in runners with alleged normal eating behavior. Int J Sports Med
26. Rencken ML, Cheatnut CH, Drinkwater BL: Bone density at multiple skeletal sites in amenorrheic athletes. JAMA
27. Csermely T, Halvax L, Schmidt E, et al.
: Occurrence of osteopenia among adolescent girls with oligo/amenorrhea. Gynecol Endocrinol
28. Matkovic V, Jelic T, Wardlow GM, et al.
: Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. Inference from a cross-sectional model. J Clin Invest
29. Ott SM: Attainment of peak bone mass. J Clin Endocrinol Metab
30. Warren MP, Brooks-Gunn J, Fox RP, et al.
: Persistent osteopenia in ballet dancers with amenorrhea and delayed menarche despite hormone therapy, a longitudinal study. Fertil Steril
31. Dugowson CE, Drinkwater BL, Clark JM: Nontraumatic femur fracture in an oligomenorrheic athlete. Med Sci Sports Exerc
32. Carbon R, Sambrook PN, Deakin V, et al.
: Bone density of elite female athletes with stress fractures. Med J Aust
33. Korpelainen R, Orava S, Karpakka J, et al.
: Risk factors for recurrent stress fractures in athletes. Am J Sports Med
34. Fagan KM: Pharmacologic management of athletic amenorrhea. Clin Sports Med
35. Cumming DC: Exercise-associated amenorrhea, low bone density, and estrogen replacement therapy. Arch Intern Med
36. Khan KM, Liu-Ambrose T, Sran MM, et al.
: New criteria for the female athlete triad syndrome? Br J Sports Med
37. Kanis JA: Diagnosis of osteoporosis and assessment of fracture risk. Lancet
38. Lauder TD, Williams MV, Campbell CS, et al.
: The female athlete triad: prevalence in military women. Military Med
39. Khan AA, Syed Z: Bone densitometry in premenopausal women: synthesis and review. J Clin Densitom
40. ISCD: Diagnosis of osteoporosis in men, premenopausal women and children. J Clin Densitom
41. Wade GN, Schneider JE, Hui-Yun L: Control of fertility by metabolic cues. Am J Physiol Endocrinol Metab
42. Laughlin GA, Yen SSC: Nutritional and endocrine-metabolic aberrations in amenorrheic athletes. J Clin Endocrinol Metab
43. Loucks AB, Mortola JF, Girton L, et al.
: Alterations in the hypothalamic-pituitary-ovarian and the hypothalamic-pituitary-adrenal axes in athletic women. J Clin Endocrinol Metab
44. De Souza MJ, McConnell HJ, O'Donnell E, et al.
: Fasting ghrelin levels in physically active women: relationship with menstrual disturbances and metabolic status. J Clin Endocrinol Metab
45. De Souza MJ, vanHeest JL, Demers L, Lasley BL: Luteal phase deficiency in recreational runners, evidence for a hypometabolic state. J Clin Endocrinol Metab
46.•• Zanker CL, Cooke CB: Energy balance, bone turnover, and skeletal health in physically active individuals. Med Sci Sports Exerc
Important review paper discussing the concept of energy deficiency, menstrual function, and skeletal health.
47. Fogelholm M, Sievanen H, Heinonen A, et al.: Association between weight cycling history and bone mineral density in premenopausal women. Osteoporos Int
48. Holbrook TL, Barrett-Connor E: The association of lifetime weight and weight control patterns with bone mineral density in an adult community. Bone Miner
49. McLean JA, Barr SI, Prior JC: Dietary restraint, exercise, and bone density in young women: are they related? Med Sci Sports Exerc
50. Compston JE, Laskey MA, Croucher PI, et al.
: Effect of diet-induced weight loss on total body bone mass. Clin Sci
51. Andersen RE, Wadden TA, Herzog RJ: Changes in bone mineral content in obese dieting women. Metabolism
52. Riggs BL, Khosla S, Atkinson EJ, et al.
: Evidence that type I osteoporosis results from enhanced responsiveness of bone to estrogen deficiency. Osteoporos Int
53. Flier JS: Is brain sympathetic to bone? Nature
54. Miller KK: Mechanisms by which nutritional disorders cause reduced bone mass in adults. J Womens Health (Larchmt)
55. Zanker C, Swaine I: Bone turnover in amenorrheic and eumenorrheic women distance runners. Scan J Med Sci Sports
56. Hotta M, Shibasaki K, Sata K, et al.
: The importance of body weight history in the occurrence and recovery of osteoporosis in patients with anorexia nervosa: evaluation by dual x-ray absorptiometry and bone metabolic markers. Eur J Endocrinol
57. Hotta M, Fukuda I, Sato K, et al.
: The relationship between bone turnover and body weight, serum insulin-like growth factor (IGF) 1, and serum IGF-binding protein levels in patients with anorexia nervosa.
58.•• Ihle R, Loucks AB: Dose-response relationships between energy availability and bone turnover in young exercising women. J Bone Min Res
2004, in press.
Important paper that discusses the effect of energy restriction on markers of bone turnover and their relationship to metabolic and reproductive hormones.
59. Parfitt AM: Skeletal heterogeneity and the purpose of bone remodeling: implications for the understanding osteoporosis. Osteoporosis.
Edited by Marcus R, Feldman D, Kelsey J. San Diego: Academic Press; 2001:443–447.